CN110651189B - Peptide vaccines - Google Patents

Abstract

The present disclosure relates to polypeptides and pharmaceutical compositions comprising polypeptides useful for preventing or treating cancer, particularly breast, ovarian and colorectal cancer. The disclosure also relates to methods of inducing a cytotoxic T cell response or treating cancer in a subject by administering a pharmaceutical composition comprising the peptide, and concomitant diagnostic methods of identifying a treated subject. The peptide comprises T cell epitopes that are immunogenic in a high percentage of patients.

Description

Peptide vaccines

Technical Field

The present disclosure relates to polypeptides and vaccines for the prevention or treatment of cancer, particularly most breast, ovarian and colorectal cancers.

Background Art

Cancer is killing millions of people worldwide because existing drugs are not yet effective in preventing or treating it. Current checkpoint inhibitor immunotherapies that reactivate existing immune responses can provide clinical benefit to a subset of cancer patients. Current cancer vaccines that induce new immune responses are poorly immunogenic and fail to benefit most patients.

A recent analysis of 63,220 unique tumors showed that due to the extensive inter-individual tumor genomic heterogeneity, cancer vaccines need to be generated specifically for each patient (Hartmaier et al. Genome Medicine 2017 9:16). Using existing technologies, it is currently not feasible to scale up HLA-specific cancer vaccines to large populations.

Summary of the invention

In antigen presenting cells (APCs), protein antigens are processed into peptides. These peptides bind to human leukocyte antigen molecules (HLA) and are presented to the cell surface of T cells as peptide-HLA complexes. Different individuals express different HLA molecules, and different HLA molecules present different peptides. Therefore, according to the prior art, if a peptide or a fragment of a larger polypeptide is presented by an HLA molecule expressed by the subject, it is identified as immunogenic to a specific human subject. In other words, the prior art describes immunogenic peptides as HLA-restricted epitopes. However, HLA-restricted epitopes induce T cell responses only in a portion of individuals expressing HLA molecules. Despite HLA allele matching, peptides that activate T cell responses in one individual are inactive in other individuals. Therefore, it was previously unknown how individual HLA molecules present antigen-derived epitopes that are activating T cell responses.

As provided herein, the multiple HLAs expressed by an individual need to present identical peptides to trigger T cell responses. The polypeptide antigen fragments that are immunogenic to a specific individual are those fragments that can be combined with multiple Class I (activation of cytotoxic T cells) or Class II (activation of helper T cells) HLAs expressed by the individual. For example, the inventors have found that the T cell epitopes that are present and combined with at least three HLA I types of the subject predict that the subject makes an immune response to the polypeptide.

Based on this discovery, the present inventors have identified T cell epitopes from certain breast cancer, ovarian cancer and/or colorectal cancer associated polypeptide antigens (cancer testis antigen (CTA)) that are capable of binding at least three HLA class I in a high proportion of individuals. These T cell epitopes or antigen fragments comprising T cell epitopes can be used to induce a specific immune response against tumor cells expressing these antigens and for treating or preventing cancer.

In a first aspect, the present disclosure provides a polypeptide comprising a fragment of up to 50 consecutive amino acids of:

(a) a colorectal cancer-associated antigen selected from TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, LEMD1, MAGE-A8, MAGE-A6 and MAGE-A3, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 21 to 40 and 234 to 250;

(b) an ovarian cancer-associated antigen selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN and AKAP-3, wherein the fragment comprises the amino acid sequence of any one of SEQ ID NOs: 272 to 301; and/or

(c) a breast cancer-associated antigen selected from PIWIL-2, AKAP-4, EpCAM, BORIS, HIWI, SPAG9, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, PRAME, NY-SAR-35, MAGE-A9, NY-BR-1, SURVIVIN, MAGE-A11, HOM-TES-85 and NY-ESO-1, wherein the above fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194.

In some specific cases, the present disclosure provides a polypeptide, which

(a) is a fragment of a colorectal cancer-associated antigen selected from TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, MAGE-A8, MAGE-A6, MAGE-A3 and LEMD1, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 21 to 40 and 234 to 250; or

(b) comprising or consisting of two or more fragments of one or more colorectal cancer associated antigens selected from TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, MAGE-A8, MAGE-A6, MAGE-A3 and LEMD1, wherein each fragment comprises a different amino acid sequence selected from any one of SEQ ID NOs: 21 to 40 and 234 to 250, optionally wherein the above fragments overlap or are arranged end to end in the polypeptide; or

(c) is a fragment of an ovarian cancer-associated antigen selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN and AKAP-3, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 272 to 301; or

(d) comprising or consisting of two or more fragments of one or more ovarian cancer-associated antigens selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN and AKAP-3, wherein each fragment comprises a different amino acid sequence selected from any one of SEQ ID NOs: 272 to 301, optionally wherein the above-mentioned fragments overlap or are arranged end to end in the polypeptide; or

(e) is a fragment of a breast cancer-associated antigen selected from SPAG9, AKAP-4, BORIS, NY-SAR-35, NY-BR-1, SURVIVIN, MAGE-A11, PRAME, MAGE-A9, HOM-TES-85, PIWIL-2, EpCAM, HIWI, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, wherein the fragment comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 20, 24, and 172 to 194; or

(f) comprising or consisting of two or more fragments of one or more breast cancer associated antigens selected from SPAG9, AKAP-4, BORIS, NY-SAR-35, NY-BR-1, SURVIVIN, MAGE-A11, PRAME, MAGE-A9, HOM-TES-8, PIWIL-2, EpCAM, HIWI, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, wherein each fragment comprises a different amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194; optionally, wherein the above-mentioned fragments overlap or are arranged end to end in the polypeptide.

In some specific cases, the polypeptide comprises or consists of a fragment of the following antigens:

(a) TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, MAGE-A8, MAGE-A6, MAGE-A3 and LEMD1;

(b) PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN and AKAP-3; and/or

(c)SPAG9, AKAP-4, BORIS, NY-SAR-35, NY-BR-1, SURVIVIN, MAGE-A11, PRAME, MAGE-A9, HOM-TES-8, PIWIL-2, EpCAM, HIWI, PLU -1, TSGA10, ODF-4, SP17, RHOXF-2;

Each fragment comprises a different amino acid sequence selected from SEQ ID NOs: 21 to 40 and SEQ ID NOs: 234 to 250; SEQ ID NOs: 272 to 301; and/or SEQ ID NOs: 1 to 20, 24 and SEQ ID NOs: 172 to 194.

In some cases, the polypeptide comprises or consists of one or more amino acid sequences selected from SEQ ID NOs:41-80, SEQ ID NOs:251-271, SEQ ID NOs:302-331, and SEQ ID NOs:196-233.

In some cases, the polypeptide comprises or consists of one or more amino acid sequences selected from SEQ ID NOs: 41-80, SEQ ID NOs: 195-233, SEQ ID NOs: 251-271, and SEQ ID NOs: 302-331, or selected from SEQ ID NOs: 81-142, 332-346, and 435-449.

In another aspect, the disclosure provides two or more polypeptide panels as described above, wherein each peptide comprises or consists of a different amino acid sequence selected from SEQ ID NOs: 21 to 40 and 234 to 250; or selected from SEQ ID NOs: 272 to 301; or selected from SEQ ID NOs: 1 to 20, 24, and 172 to 194; or selected from SEQ ID NOs: 1 to 40, 234 to 250, 272 to 301, and 172 to 194. In some cases, the polypeptide panel comprises or consists of one or more peptides comprising or consisting of an amino acid sequence of SEQ ID NOs: 130, 121, 131, 124, 134, 126, and/or SEQ ID NOs: 435 to 449.

On the other hand, the present disclosure provides a pharmaceutical composition or kit having one or more of the above-mentioned polypeptides or peptide groups as an active ingredient, or having a polypeptide comprising at least two amino acid sequences as an active ingredient, wherein the above amino acid sequences are selected from SEQ ID NOs: 21 to 40 and 234 to 250; SEQ ID NOs: 272 to 301; and/or SEQ ID NOs: 1 to 20, 24 and 172 to 194; or selected from SEQ ID NOs: 130, 121, 131, 124, 134, 126 and/or 435 to 449.

In another aspect, the present disclosure provides a method of inducing an immune response (e.g., vaccination, providing immunotherapy in a subject, or inducing a cytotoxic T cell response), the method comprising administering to the subject a pharmaceutical composition, kit, or polypeptide set as described above. The method can be a method of treating cancer, such as breast cancer, ovarian cancer, or colorectal cancer.

In other aspects, the present invention provides

The pharmaceutical composition, kit or polypeptide set as described above, for use in a method of inducing an immune response or for use in a method of treating cancer, optionally breast cancer, ovarian cancer or colorectal cancer; and

- Use of a peptide or a group of peptides as described above for the preparation of a medicament for inducing an immune response or for treating cancer, optionally breast cancer, ovarian cancer or colorectal cancer.

In another aspect, the present disclosure provides a method for identifying a human subject who may have a cytotoxic T cell response to administration of the above-mentioned pharmaceutical composition, the method comprising:

(i) determining that the active ingredient polypeptide of the pharmaceutical composition comprises a sequence of a T cell epitope capable of binding to at least three HLA class I molecules of the subject; and

(ii) identifying a subject as likely to have a cytotoxic T cell response to administration of the pharmaceutical composition.

In another aspect, the present disclosure provides a method for identifying a subject who may be clinically responsive to the above-mentioned treatment methods, the method comprising:

(i) determining that the active ingredient polypeptide comprises two or more different amino acid sequences, each of which is

a. a T cell epitope capable of binding to at least three HLA class I molecules of a subject; and

b. a fragment of a cancer associated antigen expressed by a cancer cell of the subject; and

(ii) Identifying subjects who are likely to be clinically responsive to treatment.

In another aspect, the present disclosure provides a method of determining the likelihood that a particular human subject will have a clinical response to the treatment method of claim 10, wherein one or more of the following factors corresponds to a higher likelihood of a clinical response:

(a) a higher number of amino acid sequences and/or different amino acid sequences are present in the active ingredient polypeptide, each of which is a T cell epitope capable of binding to at least three HLA class I molecules of the subject;

(b) a higher number of target polypeptide antigens comprising at least one amino acid sequence

A. is contained in the active ingredient polypeptide; and

B. is a T cell epitope capable of binding to at least three HLA class I molecules of the subject;

Optionally wherein the target polypeptide antigen is expressed in the subject, further optionally wherein the target polypeptide antigen is present in one or more samples obtained from the subject;

(c) a higher probability that the subject expresses a target polypeptide antigen, optionally a threshold amount of the target polypeptide antigen and/or optionally a target polypeptide antigen that has been determined to comprise at least one amino acid sequence that

A. is contained in the active ingredient polypeptide; and

B. is a T cell epitope capable of binding to at least three HLA class I molecules of the subject;

and/or

(d) predicting that the subject expresses a higher amount of a target polypeptide antigen, optionally a higher amount of a target polypeptide antigen expressed by the subject with a threshold probability, and/or optionally having determined a target polypeptide antigen comprising at least one amino acid sequence that

A. is contained in the active ingredient polypeptide; and

B. is a T cell epitope capable of binding to at least three HLA class I molecules of the subject.

In some cases, the cancer-associated antigen can be TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, LEMD1, MAGE-A8, MAGE-A6, MAGE-A3, PIWIL-4, WT1, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, PRAME, HIWI, PLU-1, TSGA10, ODF-4, RHOXF-2, NY-SAR-35, MAGE-A9, NY-BR-1, MAGE-A11, HOM-TES-85, NY-ESO-1 and AKAP-3. In some cases, the above method includes the step of determining that the cancer cells of the subject express one or more cancer-associated antigens. The cancer-associated antigen can be present in one or more samples obtained from the subject.

In some cases, administration of the active ingredient polypeptide of the pharmaceutical composition or kit may be selected as a method of treating a subject. The subject may be further treated by administering a pharmaceutical composition or active ingredient polypeptide.

In another aspect, the present disclosure provides a method of treatment as described above, wherein the subject has been identified as likely to have a clinical response or to have a minimum likelihood above a threshold of a clinical response to treatment as described above.

In another aspect, the present disclosure provides a method of identifying a human subject who is likely to have no clinical response to a treatment as described above, the method comprising

(i) determining that the active ingredient polypeptide of the pharmaceutical composition does not contain two or more different amino acid sequences, each of which is a T cell epitope capable of binding to at least three HLA class I molecules of the subject; and

(ii) Identifying subjects who are likely not to respond clinically to treatment.

The above method may include the step of determining the HLA class I genotype of the subject.

The present disclosure will now be described in more detail by way of example and not limitation and with reference to the accompanying drawings. When the present disclosure is given, many equivalent modifications and variations will be apparent to those skilled in the art. Therefore, the exemplary embodiments of the present invention set forth are considered to be illustrative and not restrictive. Various changes may be made to the described embodiments without departing from the scope of the present disclosure. All documents cited herein, whether above or below, are expressly incorporated herein by reference in their entirety.

The present disclosure includes combinations of the described aspects and preferred features, except where such combinations are clearly impermissible or stated to be expressly avoided. As used in this specification and the appended claims, the singular forms "a", "an" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a peptide" includes two or more such peptides.

The section headings used herein are for convenience only and are not to be construed as limiting in any way.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 ROC curves of HLA-restricted PEPI biomarkers.

Fig. 2 ROC curves for the ≥1 PEPI3+ test to determine diagnostic accuracy.

Figure 3 Distribution of HLA Class I PEPI3+ relative to CD8+T cell responses measured by prior art tests in peptide libraries used in CD8+T cell response tests. A: HLA Class I restricted PEPI3+. The 90% overall percentage of agreement (OPA) in T cell responses and PEPI3+ peptides demonstrates the use of the disclosed peptides in predicting vaccine-induced T cell response sets in individuals. B: HLA Class I restricted epitopes (PEPI1+). The OPA between the predicted epitope and CD8+T cell response was 28% (not statistically significant). Darkest gray: true positive (TP), peptide and T cell response detected; light gray: false negative (FN), only T cell response detected; lightest gray: false positive (FP), only peptide detected; dark gray: true negative (TN): neither peptide nor T cell response was detected.

Figure 4 Distribution of HLA class II PEPIs relative to CD4+ T cell responses measured by prior art assays in the peptide library used in the assay. A: HLA class II restricted PEPI4+. The OPA between PEPI4+ and CD4+ T cell responses was 67% (p=0.002). B: HLA class II restricted epitopes. The OPA between HLA class II restricted epitopes and CD4+ T cell responses was 66% (not statistically significant). Darkest gray: true positive (TP), peptide and T cell responses were detected; light gray: false negative (FN), only T cell responses were detected; lightest gray: false positive (FP), only peptides were detected; dark gray: true negative (TN): neither peptides nor T cell responses were detected.

Figure 5 Multiple HLA-binding peptides defining the HPV-16 LPV vaccine-specific T cell responder set for 18 VIN-3 and 5 cervical cancer patients. HLA class I-restricted PEPI3 counts (A and B) and HLA class II-restricted PEPI3 counts (C and D) derived from each patient's LPV antigen. Light gray: immune responders measured after vaccination in clinical trials; dark gray: immune non-responders measured after vaccination in clinical trials. The results showed that ≥3 HLA class I-binding peptides predicted CD8+ T cell reactivity, and ≥4 HLA class II-binding peptides predicted CD4+ T cell reactivity.

FIG. 6 defines multiple HLA class I binding peptides for the HPV vaccine-specific T cell response group of two patients. A: Four HPV antigens in the HPV vaccine. The box indicates the length of the amino acid sequence from the N-terminus to the C-terminus. B: Method for identifying multiple HLA binding peptides for two patients: The HLA sequence of the patient is marked with the 4-digit HLA genotype of the patient ID. The position of the first amino acid of 54 and 91 epitopes that can bind to patient 12-11 and patient 14-5 HLA (PEPI1+) respectively can be indicated by a line. PEPI2 represents a peptide selected from PEPI1+ that can bind to multiple HLAs of the patient (PEPI2+). PEPI3 represents a peptide that can bind to ≥3 HLAs of the patient (PEPI3+). PEPI4 represents a peptide that can bind to ≥4 HLAs of the patient (PEPI4+). PEPI5 represents a peptide that can bind to ≥5 HLAs of the patient (PEPI5+). PEP16 represents a peptide that can bind to 6 HLAs of the patient (PEP16). C: DNA vaccine-specific PEPI3+ group of two patients characterizing their vaccine-specific T cell responses.

FIG. 7 Correlation between ≥1 PEPI3+ scores and CTL response rates for peptide targets measured in clinical trials.

Figure 8 Correlation between ≥1 PEPI3+ score and clinical immune response rate (IRR) of immunotherapy vaccines. Dashed line: 95% confidence band.

Figure 9 Relationship between ≥2 PEPI3+ score and disease control rate (DCR) of immunotherapy vaccines. Dashed line: 95% confidence band.

Figure 10 Peptide hotspot analysis example: PRAME antigen hotspots of 433 patients in the model population. The y-axis is the 433 patients in the model population, and the x-axis is the amino acid sequence of the PRAME antigen (CTA). Each data point represents the PEPI represented by ≥3HLA class I of a patient starting from the specified amino acid position. The two most common PEPIs of the PRAME antigen (called bestEPI) are highlighted in dark gray (peptide hotspot = PEPI hotspot).

Figure 11 Calculation of CTA expression curves by analyzing the expression frequency data of tumor-specific antigens (CTA) in human breast cancer tissues. (Cell line data are not included.)

Figure 12 Breast cancer antigen expression distribution based on calculation of multi-antigen response from expression frequencies of 10 different CTAs selected. A: Non-cumulative distribution of expected values for the number of expressed antigens (AG50) calculated. This value indicates that 6.14 vaccine antigens will likely be expressed by breast tumor cells. B: Cumulative distribution curve for the minimum number of expressed antigens (CTA expression curve). This indicates that a minimum of 4 vaccine antigens will be expressed in breast cancer cells (AG95) with a probability of 95%.

Figure 13 PEPI represents antigen: Distribution of breast cancer vaccine-specific CTA antigens (referred to as "APs") with ≥1 PEPI in the model population (n=433) of breast cancer vaccine. A: Non-cumulative distribution of APs, where the average number of APs is: AP50=5.30, meaning that on average almost 6 CTAs will have PEPIs in the model population. B: Cumulative distribution curve of the minimum number of APs in the model population (n=433). This indicates that at least one vaccine antigen has a PEPI (AP95=1) in 95% of the model population (n=433).

Figure 14 PEPI represents the distribution of antigens expressed in the model population (n=433) calculated using breast cancer CTA expression rates (breast cancer vaccine-specific CTA antigens expressed by tumors, where ≥1 PEPI is predicted, referred to as "AGP"). A: Non-cumulative distribution of AGP, where the expected value of the numerically represented CTA represented by PEPI is AGP50=3.37. AGP50 is a measure of the effectiveness of the disclosed breast cancer vaccine in attacking breast tumors in an unselected patient population. AGP50=3.37 means that at least 3 CTAs from the vaccine are likely to be expressed by breast tumor cells and present PEPI in the model population. B: The cumulative distribution curve of the minimum number of AGPs in the model population (n=433) shows that at least one vaccine CTA will present PEPI in 92% of the population, and the remaining 8% of the population may have no AGP at all (AGP95=0, AGP92=1).

Figure 15 shows the CTA expression curve calculated by analyzing the expression frequency data of tumor-specific antigens (CTA) in human colorectal cancer tissues. (Cell line data are not included.)

Figure 16 Distribution of colorectal cancer antigen expression based on calculation of multi-antigen response from expression frequencies of 7 different selected CTAs. A: Non-cumulative distribution of expected values for the number of vaccine antigens expressed in colorectal cancer (AG50) calculated. This value shows that colorectal tumor cells are likely to express 4.96 vaccine antigens. B: Cumulative distribution curve for the minimum number of expressed antigens (CTA expression curve). This indicates that a minimum of 3 antigens will be expressed in colorectal cancer cells (AG95) with a probability of 95%.

Figure 17 Distribution of PEPI representative antigens (colorectal cancer vaccine specific CTA antigens where ≥1 PEPI is predicted, referred to as "AP") in a model population (n=433) of colorectal cancer. A: Non-cumulative distribution of APs, where the mean number of APs is: AP50=4.73, meaning that on average 5 CTAs will be represented by a PEPI in the model population. B: Cumulative distribution curve of the minimum number of APs in the model population (n=433). This indicates that in 95% of the model population (n=433) (AP95=2) PEPIs will represent 2 or more antigens.

Figure 18 PEPI represents the distribution of antigens expressed within the model population (n=433) calculated using colorectal cancer CTA expression rates (colorectal cancer vaccine-specific CTA antigens expressed by tumors where ≥1 PEPI is predicted, referred to as "AGP"). A: Non-cumulative distribution of AGPs, where the expected value of the numerical CTA represented by the PEPI is AGP50=2.54. AGP50 is a measure of the effectiveness of a published colorectal cancer vaccine in attacking colorectal tumors in an unselected patient population. AGP50=2.54 means that at least 2-3 CTAs from the vaccine are likely to be expressed by colorectal tumor cells and present PEPIs in the model population. B: Cumulative distribution curve of the minimum number of AGPs in the model population (n=433) showing that at least 1 vaccine CTA will be expressed and also present PEPIs in 93% of the population (AGP93=1).

FIG. 19 is a schematic diagram showing exemplary positions of amino acids in overlapping HLA class I and HLA class II binding epitopes in a 30-mer peptide.

Figure 20 Antigenicity of PolyPEP1018 CRC vaccine in the general human population. The antigenicity of PolyPEP1018 in subjects was determined by AP counts, which indicate the number of vaccine antigens that induced T cell responses in subjects. The AP counts of PolyPEP1018 were determined in each of the 433 subjects in the model population using the PEPI test, and the AP50 counts of the model population were then calculated. The AP50 of PolyPEP1018 in the model population was 4.73. The average number of immunogenic antigens (i.e., antigens with ≥1 PEPI) in PolyPEP1018 in the general population was 4.73. Abbreviation: AP = antigens with ≥1 PEPI. Left: Cumulative distribution curve. Right: Significance distribution curve.

Figure 21 Efficacy of PolyPEP1018 CRC vaccine in the general human population. If the PEPI in the vaccine is presented by tumor cells, the vaccine-induced T cells can recognize and kill the tumor cells. The number of AGPs (antigens expressed with PEPIs) is an indicator of vaccine efficacy in an individual and depends on the efficacy and antigenicity of PolyPEP1018. The average number of immunogenic CTAs (i.e., APs [expressed antigens with ≥1 PEPI]) of PolyPEP1018 in the model population was 2.54. The probability that PolyPEP1018 induces T cell responses against multiple antigens in subjects in the model population (i.e., mAGPs) is 77%.

FIG. 22 Probability of vaccine antigen expression in patient XYZ's tumor cells. The probability of 5 of the 12 target antigens in the vaccine regimen being expressed in the patient's tumor is greater than 95%. Therefore, the 12 peptide vaccines together can induce an immune response against at least 5 ovarian cancer antigens with a probability of 95% (AGP95). The probability of each peptide inducing an immune response in patient XYZ is 84%. AGP50 is mean (expected value) = 7.9 (which is a measure of the effectiveness of the vaccine in attacking patient XYZ's tumor).

FIG23 MRI findings of patient XYZ treated with personalized (PIT) vaccine. This advanced, heavily pretreated ovarian cancer patient had an unexpected objective response following PIT vaccine treatment. These MRI findings suggest that PIT vaccine combined with chemotherapy significantly reduced tumor burden. The patient now continues PIT vaccine treatment.

Figure 24 Probability of vaccine antigen expression in patient ABC tumor cells. The probability of 4 of the 13 target antigens in the vaccine being expressed in the patient's tumor is greater than 95%. Therefore, the 12 peptide vaccines can together induce an immune response against at least 4 breast cancer antigens with a probability of 95% (AGP95). The probability of each peptide inducing an immune response in patient ABC is 84%. AGP50 is the mean (expected value) of the discrete probability distribution = 6.45 (it is a measure of the effectiveness of the vaccine attacking patient ABC tumors).

Sequence Description

SEQ ID NOs: 1 to 20 list the 9-mer T cell epitopes described in Table 17.

SEQ ID NOs: 21 to 40 list the 9-mer T cell epitopes described in Table 20.

SEQ ID NOs: 41 to 60 list the 15-mer T cell epitopes described in Table 17.

SEQ ID NOs: 61 to 80 list the 15-mer T cell epitopes described in Table 20.

SEQ ID NOs: 81 to 111 list the breast cancer vaccine peptides described in Table 18a.

SEQ ID NOs: 112 to 142 list the colorectal cancer vaccine peptides described in Table 21a.

SEQ ID NOs: 143 to 158 list breast cancer, colorectal cancer and/or ovarian cancer associated antigens.

SEQ ID NOs: 159 to 171 list additional peptide sequences described in Table 10.

SEQ ID NOs: 172 to 194 list additional 9-mer T cell epitopes described in Table 17.

SEQ ID NOs: 195 to 233 list additional 15-mer T cell epitopes described in Table 17.

SEQ ID NOs: 234 to 250 list additional 9-mer T cell epitopes described in Table 20.

SEQ ID NOs: 251 to 271 list additional 15-mer T cell epitopes described in Table 20.

SEQ ID NOs: 272 to 301 list the 9-mer T cell epitopes described in Table 23.

SEQ ID NOs: 302 to 331 list the 15-mer T cell epitopes described in Table 23.

SEQ ID NOs: 332 to 346 list the ovarian cancer vaccine peptides described in Table 24.

SEQ ID NOs: 347 to 361 further list breast cancer, colorectal cancer and/or ovarian cancer associated antigens.

SEQ ID NOs: 362 to 374 list the personalized vaccine peptides designed for patient XYZ described in Table 36.

SEQ ID NOs: 375 to 386 list personalized vaccine peptides designed for ABC of the patients described in Table 39.

SEQ ID NOs: 387 to 434 list additional 9-mer T cell epitopes described in Table 32

SEQ ID NOs: 435 to 449 list additional breast cancer vaccine peptides described in Table 18a.

DETAILED DESCRIPTION

HLA genotype

HLA is encoded by most polymorphic genes of the human genome. Each person has maternal and paternal alleles of three HLA class I molecules (HLA-A*, HLA-B*, HLA-C*) and four HLA class II molecules (HLA-DP*, HLA-DQ*, HLA-DRB1*, HLA-DRB3*/4*/5*). In fact, each person expresses different combinations of 6 HLA class I molecules and 8 HLA class II molecules, which present different epitopes from the same protein antigen. The function of HLA molecules is to regulate T cell responses. However, it is not known how human HLA regulates T cell activation so far.

The nomenclature used to represent the amino acid sequence of an HLA molecule is as follows: gene name*allele:protein number, which, for example, may look like: HLA-A*02:25. In this example, "02" refers to the allele. In most cases, the allele is defined by serotype C, which means that the proteins of a given allele will not react with each other in serological assays. Protein numbers (25 in the above example) are assigned consecutively as proteins are discovered. A new protein number is assigned to any protein with a different amino acid sequence (e.g., even one amino acid change in the sequence is considered a different protein number). Further information about the nucleic acid sequence of a given locus may be appended to the HLA nomenclature, but such information is not necessary for the methods described herein.

An individual's HLA class I genotype or HLA class II genotype may refer to the actual amino acid sequence of each class I or class II HLA of the individual, or may refer to a nomenclature as described above that minimally specifies the allele and protein number of each HLA gene. The HLA genotype may be determined using any suitable method. For example, the sequence may be determined by sequencing the HLA loci using methods and protocols known in the art. Alternatively, the individual's HLA group may be stored in a database and accessed using methods known in the art.

Some subjects may have two HLA alleles encoding the same HLA molecule (e.g., two copies of HLA-A*02:25 in the case of homozygosity). The HLA molecules encoded by these alleles bind all the same T cell epitopes. For the purposes of this disclosure, as used herein, "binding to at least two HLA molecules of a subject" includes binding to HLA molecules encoded by two identical HLA alleles in a single subject. In other words, "binding to at least two HLA molecules of a subject" and the like may be additionally expressed as "binding to HLA molecules encoded by at least two HLA alleles of a subject."

Peptides

The present disclosure relates to polypeptides derived from CTA that are immunogenic to a high proportion of the human population.

As used herein, the term "polypeptide" refers to a full-length protein, a portion of a protein, or a peptide characterized by a string of amino acids. As used herein, the term "peptide" refers to a short polypeptide comprising 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15 to 10, or 11, or 12, or 13, or 14, or 15, or 20, or 25, or 30, or 35, or 40, or 45, or 50, or 55, or 60 amino acids.

As used herein, the term "fragment" or "fragment of a polypeptide" refers to a string or sequence of amino acids that is generally of reduced length relative to the above or a reference polypeptide and comprises the same amino acid sequence as the reference polypeptide in the common portion. Where appropriate, such a fragment according to the present disclosure may be included in a larger polypeptide of which it is a component. In some cases, a fragment may comprise the full length of a polypeptide, such as an entire polypeptide, such as a 9 amino acid peptide, which is a single T cell epitope. In some cases, the fragments referred to herein may contain 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 to 20, or 25, or 30, or 35, or 40, or 45, or 50 amino acids.

As used herein, the term "epitope" or "T cell epitope" refers to a continuous amino acid sequence contained within a protein antigen that has a binding affinity to (can bind to) one or more HLAs. The epitope is HLA and antigen specific (HLA epitope pair, predicted by known methods), but not subject specific. If a T cell response (cytotoxic T cell response or helper T cell response) can be induced in a specific human subject, then the epitope, T cell epitope, polypeptide, polypeptide fragment, or composition comprising a polypeptide or fragment thereof is immunogenic to the subject. In some cases, the helper T cell response is a Th1 type helper T cell response. In some cases, an epitope, T cell epitope, polypeptide, polypeptide fragment, or composition comprising a polypeptide or fragment thereof is "immunogenic" if it is more likely to induce a T cell response or immune response in a subject than a different T cell epitope (or in some cases two different T cell epitopes each) that can bind only one HLA molecule of the subject.

The terms "T cell response" and "immune response" are used interchangeably herein and refer to the activation of T cells and/or the induction of one or more effector functions following the identification of one or more HLA epitope binding pairs. In some cases, an "immune response" includes an antibody response, since HLA class II molecules stimulate auxiliary responses involved in the induction of persistent CTL responses and antibody responses. Effector functions include cytotoxicity, cytokine production, and proliferation. According to the present disclosure, a polypeptide epitope, T cell epitope, or fragment is immunogenic to a particular subject if it is able to bind to at least two, or in some cases at least three class I or at least two, or in some cases at least three or at least four class II HLA of the subject.

For the purpose of this disclosure, we propose the term "human epitope" or "PEPI" to distinguish subject-specific epitopes from HLA-specific epitopes. "PEPI" is a polypeptide fragment consisting of a continuous amino acid sequence of a polypeptide, which is a T cell epitope capable of binding to one or more HLA class I molecules of a specific human subject. In other cases, PEPI is a polypeptide fragment consisting of a continuous amino acid sequence of a polypeptide, which is a T cell epitope capable of binding to one or more HLA class II molecules of a specific human subject. In other words, "PEPI" is a T cell epitope identified by the HLA group of a specific individual. In contrast to "epitopes", PEPIs are individual-specific because different individuals have different HLA molecules that each binds to different T cell epitopes. The subject-specificity of this PEPI allows the manufacture of personalized cancer vaccines.

As used herein, "PEPI1" refers to a peptide or polypeptide fragment that can bind to one HLA class I molecule (or in certain cases, HLA class II molecule) of an individual. "PEPI1+" refers to a peptide or polypeptide fragment that can bind to one or more HLA class I molecules of an individual.

"PEPI2" refers to a peptide or polypeptide fragment that can bind to two HLA class I (or class II) molecules of an individual. "PEPI2+" refers to a peptide or polypeptide fragment that can bind to two or more HLA class I (or class II) molecules of an individual, i.e., a fragment identified according to the method of the present disclosure.

"PEPI3" refers to a peptide or polypeptide fragment that can bind to three HLA class I (or class II) molecules of an individual. "PEPI3+" refers to a peptide or polypeptide fragment that can bind to three or more HLA class I (or class II) molecules of an individual.

"PEPI4" refers to a peptide or polypeptide fragment that can bind to four HLA class I (or class II) molecules of an individual. "PEPI4+" refers to a peptide or polypeptide fragment that can bind to four or more HLA class I (or II) molecules of an individual.

"PEPI5" refers to a peptide or polypeptide fragment that can bind to five HLA class I (or class II) molecules of an individual. "PEPI5+" refers to a peptide or polypeptide fragment that can bind to five or more HLA class I (or class II) molecules of an individual.

"PEPI6" refers to a peptide or polypeptide fragment that is capable of binding to all six HLA class I (or six HLA class II) molecules in an individual.

In general, the epitope presented by HLA class I molecules is about 9 amino acids in length, and the epitope presented by HLA class II molecules is about 15 amino acids in length. However, for the purposes of this disclosure, as long as the epitope can bind to HLA, the epitope length can be more or less than 9 (for HLA class I) or more or less than 15 (for HLA class II) amino acids. For example, the epitope length that can bind to class I HLA can be 7 or 8 or 9 to 9 or 10 or 11 amino acids. The epitope length that can bind to class II HLA can be 13 or 14 or 15 to 15 or 16 or 17 amino acids.

A given subject's HLA will present only a limited number of different peptides generated by processing a protein antigen in an APC to a T cell. As used herein, "display" or "presentation" when used in relation to an HLA refers to the binding between a peptide (epitope) and an HLA. In this regard, "displaying" or "presenting" a peptide is synonymous with "binding" a peptide.

Using techniques known in the art, epitopes that will bind to a known HLA can be determined. Any suitable method can be used, provided that the same method is used to determine the multiple HLA epitope binding pairs that are directly compared. For example, biochemical analysis can be used. A list of epitopes known to be bound by a given HLA can also be used. Prediction or modeling software can also be used to determine which epitopes can be bound by a given HLA. An example is provided in Table 1. In some cases, if the IC50 or predicted IC50 of a T cell epitope is less than 5000nM, less than 2000nM, less than 1000nM or less than 500nM, then the T cell epitope can bind to a given HLA.

Table 1 Example software for determining epitope-HLA binding

In some embodiments, the peptides of the present disclosure may comprise or consist of one or more fragments of one or more CTAs. CTAs are not normally expressed outside of embryonic development in healthy cells. In healthy adults, CTA expression is limited to male germ cells that do not express HLA and cannot present antigens to T cells. Therefore, when expressed in cancer cells, CTAs are considered to be expressed neoantigens.

CTAs are good choices for cancer vaccine targets because their expression (i) is specific to tumor cells, (ii) is more frequent in metastatic tumors than in primary tumors, and (iii) is conserved among metastatic tumors in the same patient (Gajewski ed. Targeted Therapeutics in Melanoma. Springer New York. 2012)

The peptides disclosed herein may include, for example, SPAG9 (SEQ ID NO: 143), AKAP-4 (SEQ ID NO: 144), BORIS (SEQ ID NO: 145), NY-SAR-35 (SEQ ID NO: 146), NY-BR-1 (SEQ ID NO: 147), SURVIVIN (SEQ ID NO: 148), MAGE-A11 (SEQ ID NO: 149), PRAME (SEQ ID NO: 150), MAGE-A9 (SEQ ID NO: 151), HOM-TES-85 (SEQ ID NO: 152), PIWIL-2 (SEQ ID NO: 349), EpCAM (SEQ ID NO: 154), HIWI (SEQ ID NO: 350), PLU-1 (SEQ ID NO: 351), TSGA10 (SEQ ID NO: 351), ODF-4 (SEQ ID NO: 352), SP17 (SEQ ID NO: 354), RHOXF-2 (SEQ ID NO: 355), EpCAM (SEQ ID NO: 156), HIWI (SEQ ID NO: 357), PLU-1 (SEQ ID NO: 358), TSGA10 (SEQ ID NO: 359), ODF-4 (SEQ ID NO: 360), SP17 (SEQ ID NO: 361), RHOXF-2 (SEQ ID NO: 362), EpCAM (SEQ ID NO: 163), HIWI (SEQ ID NO: 364), PLU-1 (SEQ ID NO: 365), TSGA10 (SEQ ID NO: 366), ODF-4 (SEQ ID NO: 367), SP17 (SEQ ID NO: 368), RHOXF-2 (SEQ ID NO: 369), RHOXF-3 (SEQ ID NO: 370), RHOXF-3 (SEQ ID NO: 371), RHOXF-4 ( NO: 355) and NY-ESO-1 (SEQ ID NO: 356), one or more breast cancer associated antigens selected from PIWIL-4 (SEQ ID NO: 357), WT1 (SEQ ID NO: 358), EpCAM (SEQ ID NO: 154), BORIS (SEQ ID NO: 145), AKAP-4 (SEQ ID NO: 144), OY-TES-1 (SEQ ID NO: 359), SP17 (SEQ ID NO: 354), PIWIL-2 (SEQ ID NO: 349), PIWIL-3 (SEQ ID NO: 360), SPAG9 (SEQ ID NO: 143), PRAME (SEQ ID NO: 150), HIWI (SEQ ID NO: 350), SURVIVIN (SEQ ID NO: 148) and AKAP-3 (SEQ ID NO: 361), and/or one or more ovarian cancer associated antigens selected from TSP50 (SEQ ID NO: 153), EpCAM (SEQ ID NO: 154), SPAG9 (SEQ ID NO: 144). In some cases, the peptide comprises or consists of one or more fragments of one or more colorectal cancer associated antigens selected from SEQ ID NOs: 41 to 80, or one or more amino acid sequences selected from SEQ ID NOs: 41 to 80, 195 to 233, 251 to 271, and 302 to 331, which are optimized for T cell activation/binding to all HLA types in the entire population.

In some cases, the amino acid sequence is flanked at the N-terminus and/or C-terminus by additional amino acids that are not part of the target polypeptide antigen sequence, in other words, the additional amino acids are not the same sequence of consecutive amino acids adjacent to the selected fragment in the target polypeptide antigen. In some cases, the sequence is flanked at the N-terminus and/or C-terminus or between target polypeptide fragments by up to 41 or 35 or 30 or 25 or 20 or 15 or 10, or 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 or 1 additional amino acids. In other cases, each polypeptide is either composed of a fragment of the target polypeptide antigen, or is composed of two or more such fragments arranged end to end in a single peptide (arranged end to end in a peptide) or overlapping (wherein two or more fragments contain partially overlapping sequences, for example, where two PEPIs in the same polypeptide are within 50 amino acids of each other).

When fragments of different polypeptides or fragments from different regions of the same polypeptide are linked together in an engineered peptide, a new epitope may be produced around a junction (join) or a joint (junction). Such a new epitope includes at least one amino acid from each fragment on both sides of a junction or a joint, and may be referred to as a connection amino acid sequence in this article. The new epitope can induce an undesirable T cell response (autoimmunity) for healthy cells. Peptides can be designed, or polypeptides can be screened to avoid, eliminate or minimize the new epitopes corresponding to protein fragments expressed in normal healthy human cells and/or can be combined with at least two, or in some cases at least three, or at least four HLA class I molecules of a subject, or in some cases at least two, or at least three, four or five HLA class II molecules. In some cases, the above-mentioned peptides are designed or the above-mentioned polypeptides are screened to eliminate polypeptides with connection new epitopes, which can be combined with at least two HLA class I molecules expressed by individual subjects of the group in human subjects exceeding a threshold percentage in the intended treatment group. In some cases, the threshold is 20%, or 15%, or 10%, or 5%, or 2%, or 1%, or 0.5% of the population. Alignment can be determined using known methods such as the BLAST algorithm. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/).

The presence of at least two polypeptide fragments (epitopes) that can bind to at least three HLA classes I (≥2 PEPI3+) of an individual in a vaccine or immunotherapeutic composition can predict clinical response. In other words, if ≥2 PEPI3+ can be identified in the active ingredient polypeptide of the vaccine or immunotherapeutic composition, the individual may be a clinical responder. At least two multiple HLA-binding PEPIs of the composition polypeptide can target a single antigen (e.g., a polypeptide vaccine comprising two multiple HLA-binding PEPIs derived from a single tumor-associated antigen targeted by the vaccine), or different antigens (e.g., a polypeptide vaccine comprising a multiple HLA-binding PEPI derived from a tumor-associated antigen and a second multiple HLA-binding PEPI derived from a different tumor-associated antigen).

Without wishing to be bound by theory, the inventors believe that one reason for the increased likelihood of clinical benefit from vaccines/immunotherapy comprising at least two multiple HLA-binding PEPIs is that diseased cell populations, such as cancer or tumor cells or cells infected with a virus or pathogen such as HIV, are often heterogeneous within and between affected subjects. For example, a particular cancer patient may or may not express or overexpress a particular cancer-associated target polypeptide antigen of a vaccine, or their cancer may comprise a heterogeneous population of cells, some of which (over)express the antigen and some of which do not. In addition, when a vaccine/immunotherapy comprises or targets a greater number of multiple HLA-binding PEPIs, the likelihood of developing resistance is reduced because patients are less likely to develop resistance to the composition through mutations in the target PEPIs.

Most vaccines and immunotherapeutic compositions currently target only a single polypeptide antigen. However, according to the present disclosure, in some cases, it is beneficial to provide a pharmaceutical composition that targets two or more different polypeptide antigens. For example, most cancers or tumors are heterogeneous, meaning that different cancers or tumor cells of a subject (over) express different antigens. Tumor cells of different cancer patients also express different combinations of tumor-associated antigens. The most likely effective anti-cancer immunogenic compositions are those that target multiple antigens expressed by tumors in individual human subjects or populations and therefore target more cancers or tumor cells.

The beneficial effects of combining multiple bestEPIs in a single treatment (administering one or more pharmaceutical compositions containing multiple PEPIs together) can be illustrated by the personalized vaccine polypeptides described in Examples 15 and 16 below. Exemplary CTA expression probabilities in ovarian cancer are as follows: BAGE: 30%; MAGE A9: 37%; MAGE A4: 34%; MAGE A10: 52%. If patient XYZ is treated with a vaccine containing only PEPIs from BAGE and MAGE A9, the probability of having mAGP (multiple expressed antigens with PEPIs) will be 11%. If patient XYZ is treated with a vaccine containing only PEPIs from MAGE A4 and MAGE A10 CTAs, the probability of having mAGP will be 19%. However, if the vaccine contains all 4 of these CTAs (BAGE, MAGE A9, MAGE A4, and MAGEA10), the probability of having mAGP will be 50%. In other words, for two PEPI treatments, the effect will be greater than the combined probability of mAGP (probability mAGP for BAGE/MAGE, plus probability mAGP for MAGE A4 and MAGE A10). Patient XYZs PIT vaccine described in Example 15 contained an additional 9 PEPIs, so the probability of having mAGP was greater than 99.95%.

Likewise, the probabilities of expression of exemplary CTAs in breast cancer are as follows: MAGE C2: 21%; MAGE A1: 37%; SPC1: 38%; MAGE A9: 44%. The probability of mAGP for patient ABC treated with a vaccine containing only MAGE C2: 21% and PEPIs from MAGE A1 is 7%. The probability of mAGP for patient ABC treated with a vaccine containing only SPC1: 38% and PEPIs from MAGE A9 is 11%. The probability of mAGP for patient ABC treated with a vaccine containing PEPIs from MAGE C2: 21%; MAGE A1: 37%; SPC1: 38%; MAGE A9 is 44% (44>7+11). The PIT vaccine for patient ABC described in Example 16 contains an additional 8 PEPIs, so the probability of having mAGP is over 99.93%.

Thus, in some cases, a polypeptide or set of polypeptides disclosed herein, or an active ingredient polypeptide of a pharmaceutical composition or kit disclosed herein, may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 fragments of one or more cancer associated antigens or multiple CTAs such as the CTAs discussed above. Each fragment comprises or consists of a different targeting epitope having a selected from SEQ ID NOs: 1 to 40; or selected from SEQ ID NOs: 1 to 20; or selected from SEQ ID NOs: 21 to 40; or selected from SEQ ID NOs: 1 to 20, 24 and 172 to 194; or selected from SEQ ID NOs: 21 to 40 and 234 to 250; or selected from SEQ ID NOs: 272 to 301; or selected from SEQ ID NOs: 1 to 40, 172 to 194 and 234 to 250; or selected from SEQ ID NOs: 21 to 40, 234 to 250 and 272 to 301; or selected from SEQ ID NOs: 1 to 20, 24, 172 to 194 and 272 to 301; or selected from SEQ ID NOs: 1 to 40, 172 to 194, 234 to 250 and 272 to 301; or selected from SEQ ID NOs: 1 to 40, 172 to 194, 234 to 250 and 272 to 301; SEQ ID NOs: 41 to 60, 64 and 195 to 233; or selected from SEQ ID NOs: 61 to 80 and 251 to 271; or selected from SEQ ID NOs: 302 to 331; or selected from SEQ ID NOs: 41 to 80, 195 to 233 and 251 to 271; or selected from SEQ ID NOs: 61 to 80, 251 to 271 and 302 to 331; or selected from SEQ ID NOs: 41 to 60, 64, 191 to 233 and 302 to 331; or selected from SEQ ID NOs: 41 to 80, 195 to 233, 251 to 271 and 332 to 346; or selected from SEQ ID NOs: 1 to 20, 24, 41 to 60, 64, 172 to 194 and 195 to 233; or selected from SEQ ID NOs: 1 to 20, 24, 41 to 60, 64, 172 to 194 and 195 to 233; or selected from SEQ ID NOs: NO: 21 to 40, 61 to 80, 234 to 250 and 251 to 271; or selected from SEQ ID NO: 271 to 331; or selected from SEQ ID NO: 1 to 80, 172 to 194, 195 to 233, 234 to 250 and 251 to 271; or selected from SEQ ID NO: 21 to 40, 61 to 80, 234 to 250, 251 to 271, 272 to 301 and 302 to 331; or selected from SEQ ID NO: 1 to 80, 172 to 233, 234 to 271 and 272 to 331; or selected from SEQ ID NO: 81 to 111 and 435 to 449; or selected from SEQ ID NO: 112 to 142; or selected from SEQ ID NO: 332 to 346; or selected from SEQ ID NO: 81 to 142; or selected from SEQ ID NO: 332 to 346 NO: 112 to 142 and 332 to 346; or selected from SEQ ID NO: 81 to 111, 435 to 449 and 332 to 346; or selected from SEQ ID NO: 81 to 142 and 332 to 346; or selected from SEQ ID NO: 41 to 60, 64, 81 to 111, 435 to 449 and 195 to 233; or selected from SEQ ID NO: 61 to 80, 112 to 142 and 251 to 271; or selected from SEQ ID NO: 302 to 346; or selected from SEQ ID NO: 41 to 142, 195 to 233 and 251 to 271; or selected from SEQ ID NO: 61 to 80, 112 to 142, 251 to 271 and 302 to 346; or selected from SEQ ID NO: NO: 41 to 60, 64, 81 to 111, 435 to 449, 195 to 233 and 302 to 346; or selected from SEQ ID NO: 41 to 142, 195 to 233, 251 to 271 and 302 to 346; or selected from SEQ ID NO: 1 to 20, 24, 41 to 60, 64, 81 to 111, 435 to 449 and 172 to 233; or selected from SEQ ID NO: 21 to 40, 61 to 80, 112 to 142, or 234 to 271; or selected from SEQ ID NO: 272 to 346; or selected from SEQ ID NO: 1 to 142 and 172 to 271; or selected from SEQ ID NO: 21 to 40, 61 to 80, 112 to 142 and 234 to 346; or selected from SEQ ID NO: NO: 1 to 20, 24, 41 to 60, 64, 81 to 111, 435 to 449, 172 to 233 and 272 to 346; or selected from SEQ ID NO: 1 to 142 and 172 to 346; or selected from SEQ ID NO: 1 to 2, or 1 to 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or SEQ ID NO: 20 to 21, or 20 to 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31, or 32, or 33, or 34, or 35, or 36, or 37, or 38, or 39; or having an amino acid sequence selected from SEQ ID NO: NO:41 to 80, or SEQ ID NO:41 to 60, or SEQ ID NO:61 to 80; or SEQ ID NO:41 to 42, or 41 to 43, or 41 to 44, or 41 to 45, or 41 to 46, or 41 to 47, or 41 to 48, or 41 to 49, or 50, or 51, or 52, or 53, or 54, or 55, or 56, or 57, or 58, or 59, SEQ ID ... NO:60 to 61, or 60 to 62, or 60 to 63, or 60 to 64, or 60 to 65, or 60 to 66, or 60 to 67, or 60 to 68, or 60 to 69, or 60 to 70, or 60 to 71, or 60 to 72, or 60 to 73, or 60 to 74, or 60 to 75, or 60 to 76, or 60 to 77, or 60 to 78, or 60 to 79; or having a different amino acid sequence selected from SEQ ID NO: 81 to 142; or selected from SEQ ID NO: 81 to 142. NO: 81 to 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110, or 111; or selected from SEQ ID NO: 81 to 105; or selected from SEQ ID NO: 99, 100, 92, 93, 101, 103, 104, 105 and 98; or selected from SEQ ID NO: 112 to 142; or selected from SEQ ID NO: 113 to 114. NO: 112 to 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 or 142; or selected from SEQ ID NO: 112 to 134; or selected from SEQ ID NO: 121, 124, 126, 127, 130, 131, 132, 133 and 134; or selected from SEQ ID NO: or SEQ ID NO: 41 to 80; or SEQ ID NO: 41 to 60; or SEQ ID NO: 61 to 80; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID NO: 41 to 60; or SEQ ID 41 to 42, or 41 to 43, or 41 to 44, or 41 to 45, or 41 to 46, or 41 to 47, or 41 to 48, or 41 to 49, or 50, or 51, or 52, or 53, or 54, or 55, or 56, or 57, or 58, or 59, SEQ ID NO: 60 to 61, or 60 to 62, or 60 to 63, or 60 to 64, or 60 to 65, or 60 to 66, or 60 to 67, or 60 to 68, or 60 to 69, or 60 to 70, or 60 to 71, or 60 to 72, or 60 to 73, or 60 to 74, or 60 to 75, or 60 to 76, or 60 to 77, or 60 to 78, or 60 to 79; or having a different amino acid sequence selected from SEQ ID NO: 91 to 92, or 91 to 93, or 93 to 94, or 95 to 96, or 97 to 98, or 99 to 100; NO: 81 to 142; or selected from SEQ ID NO: 81 to 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110, or 111; or selected from SEQ ID NO: 81 to 105; or selected from SEQ ID NO: 99, 100, 92, 93, 101, 103, 104, 105 and 98; or selected from SEQ ID NO: 112 to 142; or selected from SEQ ID NO: 112 to 142. NO: 112 to 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 or 142; or selected from SEQ ID NO: 112 to 134; or selected from SEQ ID NO: 121, 124, 126, 127, 130, 131, 132, 133 and 134; or selected from SEQ ID NO: 130, 121, 131, 124, 134, 126; or selected from SEQ ID NO: 435 to 449; or having an amino acid sequence selected from SEQ ID NO: 435 to 449 NO:12, 32, 19 and/or 39, and/or SEQ ID NO:21, 41, 23 and/or 43 and/or SEQ ID NO:172, 177, 195 and/or 203, and/or SEQ ID NO:1, 41 and/or 197, and/or SEQ ID NO:4, 44 and/or 201, and/or SEQ ID NO:1, 4, 44, 197 and/or 201, and/or SEQ ID NO:1, 41, 197, 184 and/or 212, and/or SEQ ID NO:3, 43 and/or 200, and/or SEQ ID NO:3, 43, 200, 7 and/or 47, and/or SEQ ID NO:10, 50 and/or 220, and/or SEQ ID NO:24, 64 and/or 202, and/or SEQ SEQ ID NO: 6, 46 and/or 209, and/or SEQ ID NO: 182, 210, 185 and/or 213, and/or SEQ ID NO: 14, 54, 225 and 226, and/or SEQ ID NO: 190, 218, 11, 51 and/or 219, and/or SEQ ID NO: 12, 224 and/or 52, and/or SEQ ID NO: 192, 227 and/or 228, and/or SEQ ID NO: 17, 229, 230 and/or 57, and/or SEQ ID NO: 21, 252, 61 and/or 253, and/or SEQ ID NO: 23, 63 and/or 256, and/or SEQ ID NO: 21, 252, 61, 253, 23, 63 and/or 256, and/or SEQ ID NO: 237 and/or 238, and/or SEQ SEQ ID NO: 26 and/or 240, and/or SEQ ID NO: 242, 244, 263 and/or 265, and/or SEQ ID NO: 29, 69 and/or 259, and/or SEQ ID NO: 24, 64 and/or 255, and/or SEQ ID NO: 236, 257 and/or 258, and/or SEQ ID NO: 27, 67, 241 and/or 262, and/or SEQ ID NO: 252, 249 and/or 264, and/or SEQ ID NO: 35, 250 and/or 75, and/or SEQ ID NO: 252, 249, 264, 35, 250 and/or 75, and/or SEQ ID NO: 36, 266 and/or 76, and/or SEQ ID NO: 36, 266, 76, 39 and/or 79, and/or SEQ ID NO: NO: 38, 268 and/or 78, and/or SEQ ID NO: 38, 268, 78, 246 and/or 270, and/or SEQ ID NO: 245, 269, and/or 248, and/or SEQ ID NO: 245, 269, 248, 40 and/or 80, and/or SEQ ID NO: 272, 302, 281 and/or 311, and/or SEQ ID NO: 276, 306, 300 and/or 330, and/or SEQ ID NO: 276, 306, 289 and/or 319, and/or SEQ ID NO: 277, 307, 283 and/or 313, and/or SEQ ID NO: 277, 307, 290 and/or 320, and/or SEQ ID NO: NO:282, 312, 297 and/or 327, or other combinations of sequences of the present disclosure, which are located within 50 to 60 amino acids of each other in any one or more of the following sequences: SEQ ID NO:143 to 158 and 347 to 351; and/or SEQ ID NO:18, 19 and/or 20 and/or SEQ ID NO:34 to 40; and/or the peptides corresponding to the SEQ ID NOs shown in Tables 17, 20 and/or 23 having an N%*B% value of less than 12% or 13% or 14% or 17.6% or 17.8% or 18% or 20% or 21% or 22% or 22.2% or 24% or 25% or 27% or 28% or 30% or 31% or 31.5% or 32% or 32.5% or 35%. In some cases, the peptide group comprises or consists of one or more polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 130, 121, 131, 124, 134, 126 and/or SEQ ID NO: 435-449.

In some cases, the disclosure provides a panel or groups of any two or more peptides described above. For example, the group may include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more such peptides. In some cases, the group includes or consists of peptides that include or consist of the following: all or any combination of the amino acid sequences of SEQ ID NOs: 99, 100, 92, 93, 101, 103, 104, 105, and 98; or all or any combination of the amino acid sequences of SEQ ID NOs: 121, 124, 126, 127, 130, 131, 132, 133, and 134. In some cases, the set comprises or consists of peptides comprising or consisting of all or any combination of the amino acid sequences of SEQ ID NOs: 130, 121, 131, 124, 134, 126 and/or SEQ ID NOs: 435-449.

Immunogenicity and pharmaceutical compositions, methods of treatment and administration

In some aspects, the disclosure relates to the above-mentioned pharmaceutical compositions, kits or polypeptide groups having one or more polypeptides as active ingredients. These can be used in methods of inducing an immune response, treatment, vaccination or providing immunotherapy to a subject, and the pharmaceutical composition can be a vaccine or immunotherapy composition. This treatment includes administering one or more polypeptides or pharmaceutical compositions to the subject, the polypeptides or pharmaceutical compositions together comprising all active ingredient polypeptides in the treatment. A variety of polypeptides or pharmaceutical compositions can be administered together or sequentially, for example, all pharmaceutical compositions or polypeptides can be administered to a subject within 1 year, or 6 months, or 3 months, or 60 or 50 or 40 or 30 days.

The term "active ingredient" as used herein refers to a polypeptide intended to induce an immune response, and may include a polypeptide product of a vaccine or immunotherapy composition produced in vivo after administration to a subject. For DNA or RNA immunotherapy compositions, the polypeptide may be produced in vivo by cells of a subject to which the composition is administered. For cell-based compositions, the polypeptide may be processed and/or presented by cells of the composition, such as autologous dendritic cells or antigen presenting cells pulsed with the polypeptide or containing an expression construct encoding the polypeptide. The pharmaceutical composition may include polynucleotides or cells encoding one or more active ingredient polypeptides.

The composition/kit may optionally further include at least one pharmaceutically acceptable diluent, carrier or preservative and/or additional polypeptides that do not contain any PEPI. The polypeptide may be engineered or non-naturally occurring. The kit may include one or more separate containers, each containing one or more active ingredient peptides. The composition/kit may be a personalized medicine for preventing, diagnosing, alleviating, treating or curing an individual disease such as cancer.

In addition to one or more immunogenic peptides, the immunogenic or pharmaceutical compositions or kits described herein may also include pharmaceutically acceptable excipients, carriers, diluents, buffers, stabilizers, preservatives, adjuvants, or other substances well known to those skilled in the art. These substances are preferably non-toxic and preferably do not interfere with the pharmaceutical activity of the active ingredient. The pharmaceutical carrier or diluent can be, for example, an aqueous solution. The exact nature of the carrier or other substance may depend on the route of administration, such as oral, intravenous, cutaneous or subcutaneous, intranasal, intramuscular, intradermal, and intraperitoneal.

The pharmaceutical compositions of the present disclosure may include one or more "pharmaceutically acceptable carriers". These carriers are typically large, slowly metabolized macromolecules, such as proteins, sugars, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, sucrose (Paoletti et al., 2001, Vaccine, 19: 2118), trehalose (WO 00/56365), lactose, and lipid aggregates (e.g., oil droplets or liposomes). These carriers are well known to those of ordinary skill in the art. The pharmaceutical composition may also contain a diluent, such as water, saline, glycerol, and the like. In addition, auxiliary substances may be present, such as wetting agents or emulsifiers, pH buffer substances, and the like. Sterile, pyrogen-free phosphate-buffered saline is a typical carrier (Gennaro, 2000, Remington: The Science and Practice of Pharmacy, ^20th edition, ISBN: 0683306472).

Pharmaceutical compositions of the present disclosure can be lyophilized or aqueous forms, i.e. solutions or suspensions. This type of liquid formulation allows the compositions to be administered directly in their packaged form without the need for reconstitution in an aqueous medium, and is therefore ideal for injection. Pharmaceutical compositions can be present in vials, or they can be present in pre-filled syringes. Syringes can be with or without needles. Syringes include single doses, while vials can include single doses or multiple doses.

The liquid formulation of the present disclosure is also suitable for reconstitution of other drugs from lyophilized forms. When the pharmaceutical composition is used for such extemporaneous reconstitution, the present disclosure provides a kit that may include two vials, or may include a prefilled syringe and a vial, the contents of the syringe being used to reconstitute the contents of the vial prior to injection.

Pharmaceutical compositions of the present disclosure may include antimicrobial agents, particularly when packaged in multiple doses. Antimicrobial agents may be used, such as 2-phenoxyethanol or parabens (methyl paraben, ethyl paraben, propyl paraben). Any preservative is preferably present at a low level. Preservatives may be added exogenously and/or may be components of a large number of antigens that are mixed to form compositions (e.g., present in pertussis antigens as preservatives).

The pharmaceutical compositions of the present disclosure may include detergents, for example, Tween (polysorbate), DMSO (dimethyl sulfoxide), DMF (dimethylformamide). Detergents are typically present at low levels, such as <0.01%, but may also be used at higher levels, such as 0.01-50%.

Pharmaceutical compositions of the present disclosure may include a sodium salt (eg, sodium chloride) and free phosphate ions (eg, by using a phosphate buffer) in solution.

In certain embodiments, the pharmaceutical composition can be encapsulated in a suitable carrier to deliver the peptide to an antigen presenting cell or to increase stability. As will be appreciated by those skilled in the art, a variety of carriers are suitable for delivering the pharmaceutical composition of the present disclosure. Non-limiting examples of suitable structured fluid delivery systems may include nanoparticles, liposomes, microemulsions, micelles, dendritic polymers, and other phospholipid-containing systems. Methods for incorporating pharmaceutical compositions into delivery vehicles are known in the art.

In order to increase the immunogenicity of the composition, the pharmaceutical composition may include one or more adjuvants and/or cytokines.

Suitable adjuvants include aluminum salts such as aluminum hydroxide or aluminum phosphate, but may also be salts of calcium, iron or zinc, or may be an insoluble suspension of acylated tyrosine or acylated sugars, or may be cationically or anionically derivatized sugars, polyphosphazenes, biodegradable microspheres, monophosphoryl lipid A (MPL), lipid A derivatives (e.g., with reduced toxicity), 3-O-deacylated monophosphoryl lipid A (3D-MPL), Quil A, saponin, QS21, Freund's incomplete adjuvant (Difco Laboratories, Detroit, Michigan), Merck Adjuvant 65 (Merck, Rahway, New Jersey), AS-2 (SmithKline Beecham, Philadelphia, Pennsylvania), CpG oligonucleotides, bioadhesives and mucoadhesives, microparticles, liposomes, polyoxyethylene ether preparations, polyoxyethylene ester preparations, muramyl peptides, or imidazoquinolone compounds (e.g., imiquimod and its homologues). Human immunomodulators suitable for use as adjuvants in the present disclosure include cytokines, such as interleukins (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) can also be used as adjuvants.

In some embodiments, the composition comprises an adjuvant selected from the group consisting of Montanide ISA-51 (Seppic, Fairfield, NJ, USA), QS-21 (Aquila Biopharmaceuticals, Lexington, MA, USA), granulocyte-macrophage colony stimulating factor (GM-CSF), cyclophosphamide, bacillus Calmette-Guérin (BCG), corynbacterium parvum, levamisole, azimezone, disopyrone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete and incomplete), mineral gel, aluminum hydroxide, lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, and diphtheria toxin (DT).

For example, the cytokine may be selected from the group consisting of transforming growth factors (TGFs) such as, but not limited to, TGF-β and TGF-β, insulin-like growth factor-I and/or insulin-like growth factor-II, erythropoietin (EPO), osteoinductive factors such as, but not limited to, interferons such as, but not limited to, interferons-α, interferons-β and interferons-γ, colony stimulating factors such as, but not limited to, macrophage colony stimulating factor, granulocyte-macrophage colony stimulating factor and granulocyte colony stimulating factor. In some embodiments, the cytokine may be selected from the group consisting of nerve growth factors such as NGF-β, platelet growth factor, transforming growth factors such as, but not limited to, TGF-α and TGF-β, insulin-like growth factor-I and insulin-like growth factor-II, erythropoietin, osteoinductive factors such as, but not limited to, interferons (IFNs) such as, but not limited to, IFN-α, IFN-β and IFN-γ, colony stimulating factors such as, macrophage colony stimulating factor, granulocyte-macrophage colony stimulating factor and granulocyte colony stimulating factor. , such as but not limited to IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, interleukin (II) of IL-18, LIF, kit-ligand or FLT-3, angiostatin; thrombospondin; endostatin; tumor necrosis factor (TNF), and LT.

It is contemplated that the adjuvant or cytokine may be added in an amount of about 0.01 mg to about 10 mg per dose, preferably about 0.2 mg to about 5 mg per dose. Alternatively, the concentration of the adjuvant or cytokine may be about 0.01 to 50%, preferably about 2% to 30%.

In certain aspects, the pharmaceutical compositions of the present disclosure are prepared by physically mixing the adjuvant and/or cytokine with the PEPI under appropriate sterile conditions according to known techniques to produce the final product.

Examples of suitable compositions and methods of administration of polypeptide fragments are provided in Esseku & Adeye (2011) and Van den Mooter G (2006). The preparation of vaccines and immunotherapy compositions is generally described in "Vaccine Design" ("The subunit and adjuvant approach" (eds Powell M.F. & Newman M.J. (1995) Plenum Press New York). Fullerton describes encapsulation in liposomes in U.S. Pat. No. 4,235,877, which is also conceivable.

In some embodiments, the compositions disclosed herein are prepared as nucleic acid vaccines. In some embodiments, nucleic acid vaccines are DNA vaccines. In some embodiments, DNA vaccines or gene vaccines include plasmids with promoters and suitable transcription and translation control elements and nucleic acid sequences encoding one or more polypeptides of the present disclosure. In some embodiments, plasmids also include sequences that enhance, for example, expression levels, intracellular targeting or proteasome processing. In some embodiments, DNA vaccines include viral vectors containing nucleic acid sequences encoding one or more polypeptides of the present disclosure. In other aspects, the compositions disclosed herein include one or more nucleic acids encoding peptides that have been determined to have immunoreactivity with biological samples. For example, in some embodiments, the compositions include one or more nucleotide sequences encoding 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more peptides, and the peptides include T cell epitope fragments that can bind at least three HLA I class molecules and/or at least three HLA II class molecules of the patient. In some embodiments, peptides are derived from antigens expressed in cancer. In some embodiments, DNA or gene vaccines also encode immunomodulatory molecules to manipulate the immune response produced, such as enhancing vaccine efficacy, stimulating the immune system or reducing immunosuppression. Strategies to enhance the immunogenicity of DNA or gene vaccines include encoding of heterologous antigens, fusion of antigens with activated T cells or triggering association recognition molecules, priming with DNA vectors, then strengthening with viral vectors, and the use of immunomodulatory molecules. In some embodiments, DNA vaccines are introduced by needles, gene guns, aerosol syringes, patches, microneedles, friction and other forms. In some forms, DNA vaccines are incorporated into liposomes or other forms of nano antibodies. In some embodiments, DNA vaccines include a delivery system selected from the group consisting of transfection agents, protamine, protamine liposomes, polysaccharide particles, cationic nanoemulsions, cationic polymers, cationic polymer liposomes, cationic nanoparticles, cationic lipids and cholesterol nanoparticles, cationic lipids, cholesterol and PEG nanoparticles, dendritic polymer nanoparticles. In some embodiments, DNA vaccines are administered by inhalation or ingestion. In some embodiments, DNA vaccines are introduced into blood, thymus, pancreas, skin, muscle, tumor or other parts.

In some embodiments, the compositions disclosed herein are prepared as RNA vaccines. In some embodiments, RNA is a non-replicating mRNA or a self-amplifying RNA of viral origin. In some embodiments, non-replicating mRNA encodes peptides disclosed herein and contains 5' and 3' untranslated regions (UTR). In some embodiments, the self-amplifying RNA of viral origin not only encodes the peptides disclosed herein, but also encodes a viral replication mechanism capable of intracellular RNA amplification and a large amount of protein expression. In some embodiments, RNA is directly introduced into an individual. In some embodiments, RNA is chemically synthesized or transcribed in vitro. In some embodiments, mRNA is produced from a linear DNA template using T7, T3 or Sp6 phage RNA polymerase, and the resulting product contains an open reading frame, flanking UTR, 5' cap and poly (A) tail encoding the peptide disclosed herein. In some embodiments, various forms of 5' caps are added during or after the transcription reaction using vaccinia virus capping enzymes or by incorporating synthetic caps or anti-retrotranscription cap analogs. In some embodiments, the optimal length of the poly (A) tail is added to the mRNA directly from the encoding DNA template or by using a poly (A) polymerase. RNA encodes one or more peptides, and the peptides include fragments of T cell epitopes that can bind at least three HLA I class molecules and/or at least three HLA II class molecules of the patient. In certain embodiments, the fragment is derived from an antigen expressed in cancer. In certain embodiments, RNA includes a signal that enhances stability and translation. In certain embodiments, RNA also includes non-natural nucleotides that increase the half-life or modified nucleosides that change the immunostimulatory spectrum. In certain embodiments, RNA is introduced by a needle, a gene gun, an aerosol syringe, a patch, a microneedle, friction and other forms. In some forms, RNA vaccines are incorporated into liposomes or other forms of nano antibodies, which promote the cellular uptake of RNA and protect it from degradation. In some embodiments, the RNA vaccine comprises a delivery system selected from a transfection agent, protamine, protamine liposomes, polysaccharide particles, cationic nanoemulsions, cationic polymers, cationic polymer liposomes, cationic nanoparticles, cationic lipid and cholesterol nanoparticles, cationic lipid, cholesterol and PEG nanoparticles, dendrimer nanoparticles, and/or naked mRNA, naked mRNA electroporated in vivo, protamine complexed mRNA, mRNA associated with positively charged oil-in-water cationic nanoemulsions, mRNA associated with chemically modified dendrimers and complexed with polyethylene glycol (PEG)-lipids. , mRNA complexed with protamine in PEG-lipid nanoparticles, mRNA associated with cationic polymers such as polyethyleneimine (PEI), mRNA associated with cationic polymers such as PEI and lipid components, mRNA associated with polysaccharide (e.g., chitosan) particles or gels, mRNA in cationic lipid nanoparticles (e.g., 1,2-dioleoyloxy-3-trimethylammonium propane (DOTAP) or dioleoylphosphatidylethanolamine (DOPE) lipids), mRNA complexed with cationic lipids and cholesterol, or mRNA complexed with cationic lipids/cholesterol and PEG-lipids. In some embodiments, RNA vaccines are administered by inhalation or ingestion. In some embodiments, RNA is introduced into the blood, thymus, pancreas, skin, muscle, tumor, or other sites, and/or by intradermal, intramuscular, subcutaneous, intranasal, intranodal, intravenous, intrasplenic, intratumoral, or other delivery routes.

The polynucleotide or oligonucleotide components can be naked nucleotide sequences or combined with cationic lipids, polymers or targeting systems. They can be delivered by any available technology. For example, the polynucleotide or oligonucleotide can be introduced by needle injection, preferably intradermal, subcutaneous or intramuscular. Alternatively, delivery devices such as particle-mediated gene delivery can be used to deliver the polynucleotide or oligonucleotide directly through the skin. The polynucleotide or oligonucleotide can be topically applied to the skin or mucosal surface, for example, by intranasal, oral or rectal administration.

The uptake of polynucleotide or oligonucleotide constructs can be enhanced by several known transfection techniques, such as those involving the use of transfection agents. Examples of these agents include cationic agents such as calcium phosphate and DEAE-dextran and lipid transfection agents such as lipofectam and transfectam. The dose of the polynucleotide or oligonucleotide administered can be varied.

Administration is generally a "prophylactically effective amount" or a "therapeutically effective amount" (as the case may be, although prevention may be considered treatment), which is an amount sufficient to result in a clinical response or show a clinical benefit to the individual, such as preventing or delaying the onset of a disease or condition, ameliorating one or more symptoms, inducing or prolonging remission, or delaying relapse or recurrence.

The dosage can be determined according to various parameters, in particular, according to the substance used, the age, weight and condition of the individual to be treated, the route of administration, and the desired regimen. The amount of antigen in each dose is selected as the amount of inducing an immune response. The doctor can determine the route of administration and dosage required for any particular individual. The dosage can be provided as a single dose or can be provided as multiple doses, such as taken at regular intervals, such as 2, 3 or 4 doses per hour. Typically, peptides, polynucleotides or oligonucleotides are typically administered in the range of 1pg to 1mg, more typically 1pg to 10μg for particle-mediated delivery, and in the range of 1μg to 1mg, more typically 1μg to 100μg, more typically 5μg to 50μg for other routes. Typically, it is expected that each dose will contain 0.01mg to 3mg antigen. The optimal amount of a specific vaccine can be determined by studies involving observations of immune responses in subjects.

Examples of the above techniques and protocols can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.

In some cases according to the present disclosure, more than one peptide or peptide composition is administered. Two or more pharmaceutical compositions can be administered together/simultaneously and/or at different times or in sequence. Therefore, the present disclosure includes multiple groups of pharmaceutical compositions and uses thereof. The use of a combination of different peptides that optionally target different antigens is important for overcoming the challenges of tumor genetic heterogeneity and individual HLA heterogeneity. The combined use of the peptides disclosed herein expands the group of individuals who can experience clinical benefits from vaccination. The combined use of the peptides disclosed herein expands the population of individuals who can experience clinical benefits from vaccination. The pharmaceutical composition of multiple PEPIs manufactured for a regimen can define a drug product.

The route of administration includes, but is not limited to, intranasal, oral, subcutaneous, intradermal and intramuscular. Subcutaneous administration is particularly preferred. Subcutaneous administration can be, for example, by injection into the sides and front of the abdomen, upper arm or thigh, the scapular region of the back or the upper abdominal gluteal region.

Compositions of the present disclosure can also be administered in one or more dosages and by other routes of administration. For example, these other routes include intradermal, intravenous, intravascular, intraarterial, intraperitoneal, intrathecal, intratracheal, intracardiac, intralobar, intramedullary, intrapulmonary and intravaginal. Depending on the desired duration of treatment, compositions according to the present disclosure can be administered once or multiple times, and can also be administered intermittently, such as monthly administration for several months or years, and administered with different dosages.

Solid dosage forms for oral administration include capsules, tablets, caplets, pills, powders, micropills and granules. In such solid dosage forms, the active ingredient is usually combined with one or more pharmaceutically acceptable excipients, examples of which are described in detail above. Oral preparations can also be administered as aqueous suspensions, elixirs or syrups. For this reason, the active ingredient can be combined with various sweeteners or flavorings, coloring agents and emulsifiers and/or suspending agents if needed, and diluents such as water, ethanol, glycerol and combinations thereof.

One or more compositions of the present invention may be administered alone or in combination with other pharmacological compositions or treatments (e.g., chemotherapy and/or immunotherapy and/or vaccines), or methods of treatment and uses according to the present invention may be performed. Other therapeutic compositions or treatments may be, for example, one or more of those discussed herein, and may be administered simultaneously or sequentially (before or after) with the compositions or treatments disclosed herein.

In some cases, the treatment can be administered in combination with checkpoint blockade therapy/checkpoint inhibitors, co-stimulatory antibodies, cytotoxic or non-cytotoxic chemotherapy and/or radiotherapy, targeted therapy or monoclonal antibody therapy. Chemotherapy has been shown to sensitize tumors to specific cytotoxic T cell killing induced by vaccination (Ramakrishnan et al. J. Clin. Invest. 2010; 120 (4): 1111-1124). Examples of checkpoint inhibitors are CTLA-4 inhibitors, Ipilimumab and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) signaling inhibitors, Nibolumab, Pembrolizumab, Atezolizumab and Durvalumab. Examples of chemotherapeutic agents include alkylating agents, including nitrogen mustards such as dichloromethyldiethylamine (HN2), cyclophosphamide, ifosfamide, melphalan (L-sarcosine protease), and chlorambucil; anthracyclines; epothilones; nitrosoureas such as carmustine (BCNU), lomustine (CCNU), semustine (methyl CCNU), and streptozotocin (streptozotocin); triazenes such as dacarbazine (DTIC); dimethyltriazene imidazole carboxamide; ethyleneimines/methylmelamines such as hexamethylmelamine, thiotepa; alkyl sulfonates such as busulfan; antimetabolites including phyllotoxin; Acid analogs such as methotrexate (methotrexate); alkylating agents, antimetabolites, pyrimidine analogs such as fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorodeoxyuridine; FUdR) and cytosine arabinoside (cytosine arabinoside); purine analogs and related inhibitors, such as mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG) and pentostatin (2′-deoxycoformycin); epipodophyllotoxins; enzymes such as L-asparaginase; biological response modifiers, such as IFNα, IL-2, G-CSF and GM-CSF; platinum coordination complexes such as cisplatin (cisplatin); is-DDP), oxaliplatin and carboplatin; anthracenediones such as mitoxantrone and anthracyclines; substituted ureas such as hydroxyurea; methylhydrazine derivatives including methylprocarbazine (N-methylhydrazine, MIH) and methylprocarbazine; adrenocortical suppressants such as mitotane (o,p′-DDD) and aminoglutethimide; paclitaxel and analogs/derivatives; hormones/hormone therapies and agonists/antagonists including adrenocortical steroid antagonists such as prednisone and its equivalents, dexamethasone and aminoglutethimide, progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate, estrogens such as diethylstilbestrol and ethinyl estradiol equivalents, antiestrogens such as Tamoxifen, androgens including testosterone propionate and fluoxymesterone/equivalents, antiandrogens such as flutamide, gonadotropin-releasing hormone analogs and leuprolide, and nonsteroidal antiandrogens such as flutamide; natural products including vinca alkaloids such as vinblastine (VLB) and vincristine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin (actinomycin D), daunorubicin (daunorubicin; erythromycin), doxorubicin, bleomycin, plicamycin (mithramycin) and mitomycin (mitomycin C), enzymes such as L-asparaginase, and biological response modifiers such as interferon alphenome.

In some cases, the method of treatment is a method of vaccination or a method of providing immunotherapy. As used herein, "immunotherapy" is to prevent or treat a disease or condition by inducing or enhancing an immune response in an individual. In certain embodiments, immunotherapy refers to a therapy including administering one or more drugs to an individual to cause a T cell response. In a specific embodiment, immunotherapy refers to a therapy including administering or expressing a polypeptide containing one or more PEPIs to an individual to cause a T cell response, thereby identifying and killing cells that display one or more PEPIs bound to class I HLA on its cell surface. In another specific embodiment, immunotherapy includes administering one or more PEPIs to an individual to cause a cytotoxic T cell response for cells, which cells display tumor-associated antigens (TAA) or cancer testis antigens (CTA) containing one or more PEPIs on the cell surface. In another embodiment, immunotherapy refers to a therapy including administering or expressing a polypeptide containing one or more class II HLA-presented PEPIs to an individual to cause a helper T cell response, thereby providing costimulation to the cytotoxic T cells that identify and kill diseased cells, which display one or more PEPIs bound to class I HLA on their cell surfaces. In another specific embodiment, immunotherapy refers to a therapy that includes administering to an individual one or more drugs that reactivate existing T cells to kill target cells. The theory is that the cytotoxic T cell response will eliminate cells displaying one or more PEPIs, thereby improving the clinical condition of the individual. In some cases, immunotherapy can be used to treat tumors. In other cases, immunotherapy can be used to treat diseases or disorders based on intracellular pathogens.

In some cases, the disclosure relates to the treatment of cancer or the treatment of solid tumors. In some cases, treatment is for breast cancer, ovarian cancer or colorectal cancer. In other cases, treatment can be directed to any other cancer or solid tumor that expresses a target tumor-associated antigen of the peptides of the present invention as described herein, or any cancer that expresses such a target polypeptide antigen in some or a high percentage of subjects. Treatment can be directed to cancer or malignant or benign tumors of any cell, tissue or organ type. Cancer may or may not be metastatic. Exemplary cancers include carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors or blastomas. Cancer may or may not be hormone-related or dependent cancers (e.g., estrogen or androgen-related cancers).

Peptide and patient selection

Specific polypeptide antigens, particularly short peptides derived from these antigens commonly used for vaccination and immunotherapy, induce immune responses in only a portion of human subjects. The polypeptides disclosed herein are specifically selected to induce immune responses in a high proportion of the general population, but due to HLA genotype heterogeneity, they may not be effective in all individuals. HLA genotype population heterogeneity refers to the fact that the immune or clinical response rates to the vaccines described herein are different between different human subpopulations.

The present disclosure also provides a method of identifying a human subject (a potential responder) who is likely to have a cytotoxic T cell response to administration of a pharmaceutical composition comprising a peptide of the present disclosure or predicting the likelihood that a subject will have a cytotoxic T cell response.

As provided herein, it is generally necessary for a variety of HLAs of an individual to present T cell epitopes to trigger T cell responses. The best predictor of the cytotoxic T cell response to a given polypeptide determined by the inventors is the presence of at least one T cell epitope (≥1 PEPI3+) presented by three or more HLA classes of an individual. Therefore, the presence of one or more T cell epitopes that can be combined with at least three HLAs of a subject in the active ingredient peptide of a pharmaceutical composition indicates that the subject has a cytotoxic T cell response to administering a pharmaceutical composition. The subject may be an immunoresponder.

In some cases, the T cell epitope capable of binding to at least three HLA class I molecules of the subject has an amino acid sequence of SEQ ID NOs: 1 to 40, or any one of SEQ ID NOs: 1 to 40, 172 to 194, 234 to 250, and 272 to 301. In other cases, the T cell epitope may have different amino acid sequences within one or more peptides of the pharmaceutical composition.

The inventors have also found that the presence of at least two epitopes in a vaccine or immunotherapy composition that can bind to at least three HLAs of an individual can predict clinical response. In other words, if an individual has a total of ≥2 PEPI3+ in the active ingredient polypeptide of the vaccine or immunotherapy composition, and these PEPI3+ are derived from antigen sequences that are actually expressed in the individual (e.g., the target tumor cells of the individual express the target tumor-associated antigen), then the individual is a possible clinical responder (i.e., a clinically relevant immune responder).

Therefore, some aspects of the present disclosure relate to a method for identifying that a subject may have a clinical response to a method of treating a disease according to the present disclosure, or predicting that a subject will have a possibility of a clinical response. "Clinical response" or "clinical benefit" as used herein can be to prevent or delay the onset of a disease or condition, improve one or more symptoms, induce or prolong remission, or delay recurrence or recurrence or deterioration, or any other improvement or stabilization of a subject's disease state. Where appropriate, "clinical response" can be related to "disease control" or "objective response" defined in the "Response Evaluation Criteria for Solid Tumors" (RECIST) guidelines.

In some embodiments, the method includes determining that one or more cancer-associated antigens selected from SPAG9, AKAP-4, BORIS, NY-SAR-35, NY-BR-1, SURVIVIN, MAGE-A11, PRAME, MAGE-A9, HOM-TES-85, TSP50, EpCAM, CAGE1, FBXO39, MAGE-A8, and MAGE-A6 are expressed by cancer. For example, the expression of cancer-associated antigens can be detected in a sample (e.g., a tumor biopsy) obtained from a subject using methods known in the art.

The inventors have found that it is not enough for a vaccine or immunotherapy composition to target an antigen expressed by a patient's cancer or tumor cells, nor is it enough for the target sequence of the antigen to bind to the patient's HLA class I (HLA restricted epitope). The composition may be effective only in patients of three or more HLA classes that both express the target antigen and have a single T cell epitope that binds the target antigen. In addition, as described above, at least two epitopes that are combined with at least 3 HLAs of the patient are usually required to induce a clinically relevant immune response.

Therefore, the method further includes determining that the active ingredient peptide of the pharmaceutical composition comprises two or more different amino acid sequences, each amino acid sequence is a) a fragment of a cancer associated antigen expressed by a subject's cancer cell determined as described above; and b) is capable of binding to at least three HLA classes I T cell epitopes of the subject.

In some cases, the T cell epitope capable of binding to at least three HLA class I of the subject has an amino acid sequence of SEQ ID NOs: 1 to 40, or any one of SEQ ID NOs: 1 to 40, 172 to 194, 234 to 250, and 272 to 301. In other cases, the T cell epitope may have different amino acid sequences within one or more peptides of the pharmaceutical composition.

In some cases, the possibility that a subject has a clinical response to a peptide vaccine or immunotherapy composition such as those described herein can be determined without knowing whether the target antigen is expressed in the subject's cancer or tumor cells and/or determining the subject's HLA I class genotype. The known frequencies of HLA class I and class II genotypes of the subject in the disease known antigen expression frequency (such as MAGE-A3 in tumor types such as breast cancer or colorectal cancer) and/or target populations (such as common populations, diseased populations) can be used alternatively. In addition, as identified and described herein, by combining the peptides (BestEPI) of the PEPI with the highest presentation frequency in the target antigens of multiple high-frequency expressions in the disease, it is possible to design a cancer vaccine regimen effective for a high proportion of patients. However, using the companion diagnostic method described herein to preselect the patient most likely to have a clinical response will increase the clinical response rate in the treated patient.

The probability of a subject responding to treatment is increased by (i) presenting more multiple HLA-binding PEPIs in the active ingredient polypeptide; (ii) presenting PEPIs in more target polypeptide antigens; and (iii) expression of the target polypeptide antigen in the subject or the subject's diseased cells. In some cases, the expression of the target polypeptide antigen in the subject may be known, for example if the target polypeptide antigen is present in a sample obtained from the subject. In other cases, population expression frequency data, such as the probability of antigen expression in breast cancer, ovarian cancer, or colorectal cancer, can be used to determine the probability that a particular subject or a diseased cell of a particular subject (over) expresses a particular or any combination of target polypeptide antigens. Population expression frequency data may involve a population of subjects and/or disease matches or a population intended for treatment. For example, the frequency or probability of expression of a specific cancer-associated antigen in a specific cancer or a subject with a specific cancer (e.g., breast cancer) can be determined by detecting the antigen in a tumor (e.g., a breast cancer tumor sample). In some cases, such expression frequencies can be determined from published digital and scientific publications. In some cases, the method of the present invention includes a step of determining the expression frequency of a relevant target polypeptide antigen in a relevant population.

Disclosed are a series of pharmacodynamic biomarkers that predict the activity/effect of vaccines in individual human subjects as well as in populations of human subjects. The biomarkers have been developed specifically for cancer vaccines, but similar biomarkers can be used for other vaccines or immunotherapy compositions. Exemplary biomarkers are as follows.

AG95 - Vaccine efficacy: The number of antigens in a cancer vaccine that are expressed with 95% probability by a specific tumor type. AG95 is an indicator of vaccine efficacy and is independent of the immunogenicity of the vaccine antigens. AG95 is calculated based on tumor antigen expression rate data. These data can be obtained from experiments published in peer-reviewed scientific journals. Technically, AG95 is determined by the binomial distribution of antigens in the vaccine and takes into account all possible variations and expression rates.

PEPI3+ count - Immunogenicity of the vaccine in a subject: Vaccine-derived PEPI3+ is a personal epitope that binds to at least 3 HLAs of a subject and induces a T cell response. PEPI3+ can be determined using a PEPI3+ test in subjects with a known full 4-digit HLA genotype.

AP count - antigenicity of the vaccine in the subject: the number of vaccine antigens that have PEPI3+. The vaccine contains sequences from target polypeptide antigens expressed by diseased cells. The AP count is the number of antigens in the vaccine that have PEPI3+. The AP count represents the number of antigens in the vaccine that can induce a T cell response in the subject. The AP count characterizes the vaccine-antigen-specific T cell response of the subject because it depends only on the HLA genotype of the subject and is independent of the subject's disease, age, and drug treatment. The correct value is between 0 (no antigen presents PEPI) and the maximum number of antigens (all antigens present PEPI).

AP50 - antigenicity of vaccine in a population: average number of vaccine antigens with PEPI in a population. AP50 is suitable for characterizing vaccine-antigen-specific T cell responses in a given population, as it depends on the HLA genotype of the subjects in the population.

AGP count - vaccine efficacy in subject: the number of vaccine antigens expressed in tumors with PEPIs. The AGP count represents the number of tumor antigens that the vaccine recognized and induced a T cell response (hit the target). The AGP count depends on the vaccine-antigen expression rate in the subject's tumor and the subject's HLA genotype. Correct values are between 0 (no PEPIs expressing antigen presentation) and the maximum number of antigens (all antigens are expressed and present PEPIs).

·AGP50 - Vaccine efficacy for cancer in a population: The average number of vaccine antigens expressed in a specified tumor with PEPI (ie, AGP) in a population. AGP50 represents the average number of tumor antigens that can be identified by a vaccine-induced T cell response. AGP50 depends on the expression rate of the antigen in the tumor type shown and the immunogenicity of the antigen in the target population. AGP50 can assess the efficacy of vaccines in different populations and can be used to compare different vaccines in the same population. The calculation of AGP50 is similar to that for AG50, except that expression is weighted by the presence of PEPI3+ on the vaccine antigen expressed in the subject. In a theoretical population where each subject has a PEPI from each vaccine antigen, AGP50 will be equal to AG50. In another theoretical population, where no subject has a PEPI from any vaccine antigen, AGP50 will be 0. In general, the following statements are valid: 0≤AGP50≤AG50.

mAGP - Candidate biomarker for selecting likely responders: The probability that a cancer vaccine induces a T cell response against multiple antigens expressed in a given tumor. mAGP is calculated, for example, by the expression rate of vaccine-antigens in the tumor and the presentation rate of vaccine-derived PEPIs in the subject. Technically, mAGP is the sum of the probabilities of multiple AGPs (≥2AGPs) based on the AGP distribution.

The results of the above predictions can be used to inform doctors about the decision of the subject's treatment. Therefore, in some cases, the method of the present disclosure predicts that the subject will have or may have a T cell response and/or clinical response for treatment as described herein, and the method further includes selecting the treatment for human subjects. In some cases, if the probability of the response of the subject's target predetermined number of target polypeptide antigens (optionally wherein the target polypeptide antigen is (predicted) expressed) is higher than a predetermined threshold, the subject is selected for treatment. In some cases, the number of target polypeptide antigens or epitopes is 2. In some cases, the number of target polypeptide antigens or epitopes is 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. The method may further include executing the treatment regimen to human subjects. Alternatively, the method can predict that the subject will not have an immune response and/or clinical response, and further includes selecting different treatment regimens for the subject.

Other embodiments of the present disclosure: (1)

1. A pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 112 to 142.

2. The pharmaceutical composition according to item 1, comprising 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, or 6 or more peptides.

3. The pharmaceutical composition according to item 1, comprising two peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 121 and 124.

4. The pharmaceutical composition according to item 1, comprising four peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 126, 130, 131 and 134.

5. The pharmaceutical composition according to item 1, comprising six peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 121, 124, 126, 130, 131 and 134.

6. The pharmaceutical composition according to item 5, further comprising at least one additional peptide comprising a fragment of an antigen selected from TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, MAGE-A8 and MAGE-A6.

7. The pharmaceutical composition according to item 5, further comprising one or more additional peptides, each of the one or more additional peptides comprising a different amino acid sequence of any one of SEQ ID NOs: 112-120, 122, 123, 125, 127-129, 132, 133 and 135-142.

8. The pharmaceutical composition according to item 1, further comprising a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

9. The pharmaceutical composition according to item 8, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

10. A pharmaceutical composition comprising one or more nucleic acid molecules encoding one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 112 to 142.

11. A method of identifying and treating a human subject with cancer who is likely to have a clinical response to administration of a pharmaceutical composition according to item 1, comprising

(i) measuring a biological sample of a subject to determine the subject's HLA genotype;

(ii) determining that the pharmaceutical composition comprises two or more sequences that are T cell epitopes capable of binding to at least three HLA class I molecules of the subject;

(iii) determining the probability that the subject's tumor expresses one or more antigens corresponding to the T cell epitopes identified in step (ii) using the population expression data for each antigen to identify the likelihood that the subject will have a clinical response to administration of the pharmaceutical composition; and

(iv) administering the composition described in item 1 to the identified subject.

12. The method according to item 11, wherein the subject has colorectal cancer.

13. The method according to item 11, wherein the pharmaceutical composition comprises 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, or 6 or more peptides.

14. The method according to item 11, wherein the pharmaceutical composition comprises two peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 121 and 124.

15. The method according to item 11, wherein the pharmaceutical composition comprises four peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 126, 130, 131 and 134.

16. The method according to item 11, wherein the pharmaceutical composition comprises six peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 121, 124, 126, 130, 131 and 134.

17. The method according to item 11, wherein the pharmaceutical composition further comprises at least one additional peptide comprising a fragment of an antigen selected from TSP50, EpCAM, SPAG9, CAGE1, FBXO39, SURVIVIN, MAGE-A8 and MAGE-A6.

18. The method of item 11, wherein the pharmaceutical composition further comprises one or more additional peptides, each of the one or more additional peptides comprising a different amino acid sequence of any one of SEQ ID NOs: 112 to 120, 122, 123, 125, 127 to 129, 132, 133, and 135 to 142.

19. The method according to item 11, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

20. The method according to item 19, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

21. The method of item 11, further comprising administering to the identified subject a chemotherapeutic agent, a checkpoint inhibitor, a targeted therapeutic agent, a radiotherapeutic agent, another immunotherapeutic agent, or a combination thereof.

22. The method according to item 13, further comprising before the applying step,

(i) assaying a tumor sample from a subject to determine that three or more peptides of the pharmaceutical composition comprise two or more different amino acid sequences, each of which is

a. a fragment of a cancer associated antigen expressed by a cancer cell of the subject as determined in step (i); and

b. a T cell epitope capable of binding to at least three HLA class I molecules of a subject; and

(ii) confirming that the subject is likely to have a clinical response to treatment.

Other embodiments of the present disclosure——(2)

Breast cancer

1. A pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 81 to 111 and 435 to 449.

2. The pharmaceutical composition according to item 1, comprising 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, or 12 or more peptides.

3. The pharmaceutical composition according to item 1, comprising 9 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 92, 93, 98, 99 to 101 and 103 to 105.

4. The pharmaceutical composition according to item 1, further comprising at least one additional peptide, wherein the additional peptide comprises an antigenic fragment selected from PIWIL-2, AKAP-4, EpCAM, BORIS, HIWI, SPAG9, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, PRAME, NY-SAR-35, MAGE-A9, NY-BR-1, SURVIVIN, MAGE-A11, HOM-TES-85 and NY-ESO-1.

5. The pharmaceutical composition according to item 4, wherein the antigen fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194.

6. The pharmaceutical composition according to item 4, wherein the antigen fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 41 to 60 and 195 to 233.

7. The pharmaceutical composition according to item 1, further comprising a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

8. The pharmaceutical composition according to item 7, wherein the adjuvant is selected from the group consisting of: Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

9. A pharmaceutical composition comprising one or more nucleic acid molecules encoding one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 81 to 111 and 435 to 449.

10. The pharmaceutical composition of item 9, wherein the one or more nucleic acid molecules encode 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, or 12 or more peptides.

11. The pharmaceutical composition according to item 9, wherein the one or more nucleic acid molecules encode 9 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 92, 93, 98, 99 to 101 and 103 to 105.

12. The pharmaceutical composition according to item 9, wherein the one or more nucleic acid molecules encode at least one additional peptide, wherein the additional peptide comprises an antigenic fragment selected from PIWIL-2, AKAP-4, EpCAM, BORIS, HIWI, SPAG9, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, PRAME, NY-SAR-35, MAGE-A9, NY-BR-1, SURVIVIN, MAGE-A11, HOM-TES-85 and NY-ESO-1.

13. The pharmaceutical composition according to item 12, wherein the antigen fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194.

14. The pharmaceutical composition according to item 12, wherein the antigen fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 41 to 60 and 195 to 233.

15. The pharmaceutical composition according to item 9, further comprising a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

16. The pharmaceutical composition according to item 15, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

17. A method for identifying and treating a human subject with cancer who may have a clinical response to administration of a pharmaceutical composition according to item 1, the method comprising

(i) measuring a biological sample of a subject to determine the subject's HLA genotype;

(ii) determining that the pharmaceutical composition comprises two or more sequences that are T cell epitopes capable of binding to at least three HLA class I molecules of the subject;

(iii) determining the probability that the subject's tumor expresses one or more antigens corresponding to the T cell epitopes identified in step (ii) using the population expression data for each antigen to identify the likelihood that the subject will have a clinical response to administration of the pharmaceutical composition; and

(iv) administering the composition of item 1 to the identified subject.

18. The method of item 17, wherein the subject suffers from breast cancer.

19. The method of item 17, wherein the pharmaceutical composition comprises 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, or 12 or more peptides.

20. The method according to item 17, wherein the pharmaceutical composition comprises 9 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 92, 93, 98, 99 to 101 and 103 to 105.

21. The method according to item 17, wherein the pharmaceutical composition further comprises at least one additional peptide, wherein the additional peptide comprises an antigenic fragment selected from PIWIL-2, AKAP-4, EpCAM, BORIS, HIWI, SPAG9, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, PRAME, NY-SAR-35, MAGE-A9, NY-BR-1, SURVIVIN, MAGE-A11, HOM-TES-85 and NY-ESO-1.

22. The method according to item 21, wherein the antigenic fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194.

23. The method according to item 21, wherein the antigenic fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 41 to 60 and 195 to 233.

24. The method according to item 17, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

25. The pharmaceutical composition according to item 24, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

26. The method of clause 17, further comprising administering to the identified subject a chemotherapeutic agent, a checkpoint inhibitor, a targeted therapy agent, a radiation therapy agent, another immunotherapeutic agent, or a combination thereof.

27. The method according to item 17, further comprising before the applying step,

(iii) assaying a tumor sample from the subject to determine that the three or more peptides of the pharmaceutical composition comprise two or more different amino acid sequences, wherein each amino acid sequence is

a. a fragment of a cancer associated antigen expressed by a cancer cell of the subject as determined in step (i); and

b. a T cell epitope capable of binding to at least three HLA class I molecules of a subject; and

(iv) confirming that the subject is likely to have a clinical response to treatment.

28. A method of identifying and treating a human subject with cancer that may be immune responsive to administration of a pharmaceutical composition according to item 1, comprising

(i) measuring a biological sample of a subject to determine the subject's HLA genotype;

(ii) determining that the pharmaceutical composition comprises one or more sequences that are T cell epitopes capable of binding to at least three HLA class I molecules of the subject; and

(iii) administering the composition of item 1 to the identified subject.

29. A kit comprising:

A. A first pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 81 to 111 and 435 to 449; and

b. a different second pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 81 to 111 and 435 to 449.

30. A pharmaceutical composition comprising: a nucleic acid molecule expressing two or more polypeptides, each polypeptide comprising a fragment of up to 50 consecutive amino acids of an antigen selected from PIWIL-2, AKAP-4, EpCAM, BORIS, HIWI, SPAG9, PLU-1, TSGA10, ODF-4, SP17, RHOXF-2, PRAME, NY-SAR-35, MAGE-A9, NY-BR-1, SURVIVIN, MAGE-A11, HOM-TES-85 and NY-ESO-1, wherein each fragment comprises a different amino acid sequence selected from any one of SEQ ID NOs: 1 to 20, 24 and 172 to 194.

31. A pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 332 to 346.

32. The pharmaceutical composition according to item 31, comprising 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, 12 or more peptides, 13 or more peptides, 14 or more peptides, or 15 or more peptides.

33. The pharmaceutical composition according to item 31, comprising 15 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 332 to 346.

34. The pharmaceutical composition according to item 31, further comprising at least one additional peptide comprising an antigenic fragment selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN, and AKAP-3.

35. The pharmaceutical composition according to item 34, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 272 to 301.

36. The pharmaceutical composition according to item 34, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 302 to 331.

37. The pharmaceutical composition according to item 31, further comprising a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

38. The pharmaceutical composition according to item 37, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

39. A pharmaceutical composition comprising one or more nucleic acid molecules encoding one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 332 to 346.

40. The pharmaceutical composition of item 39, wherein the one or more nucleic acid molecules encode 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, 12 or more peptides, 13 or more peptides, 14 or more peptides, or 15 or more peptides.

41. The pharmaceutical composition according to item 39, wherein the one or more nucleic acid molecules encode 15 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 332 to 346.

42. The pharmaceutical composition of item 39, wherein the one or more nucleic acid molecules encode at least one additional peptide, wherein the additional peptide comprises an antigenic fragment selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN, and AKAP-3.

43. The pharmaceutical composition according to item 42, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 272 to 301.

44. The pharmaceutical composition according to item 42, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 302 to 331.

45. The pharmaceutical composition according to item 39, further comprising a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

46. The pharmaceutical composition according to item 45, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

47. A method of identifying and treating a human subject with cancer who is likely to have a clinical response to administration of a pharmaceutical composition according to item 28, the method comprising

(i) measuring a biological sample of a subject to determine the subject's HLA genotype;

(ii) determining that the pharmaceutical composition comprises two or more sequences that are T cell epitopes capable of binding to at least three HLA class I molecules of the subject;

(iii) determining the probability that the subject's tumor expresses one or more antigens corresponding to the T cell epitopes identified in step (ii) using the population expression data for each antigen to identify the likelihood that the subject will have a clinical response to administration of the pharmaceutical composition; and

(iv) administering the composition of item 28 to the identified subject.

48. The method of item 47, wherein the subject has ovarian cancer.

49. The method of item 47, wherein the pharmaceutical composition comprises 2 or more peptides, 3 or more peptides, 4 or more peptides, 5 or more peptides, 6 or more peptides, 7 or more peptides, 8 or more peptides, 9 or more peptides, 10 or more peptides, 11 or more peptides, 12 or more peptides, 13 or more peptides, 14 or more peptides, or 15 or more peptides.

50. The method according to item 47, wherein the pharmaceutical composition comprises 15 peptides, wherein each peptide comprises a different amino acid sequence of SEQ ID NO: 332 to 346.

51. The method of item 47, wherein the pharmaceutical composition further comprises at least one additional peptide comprising an antigenic fragment selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN, and AKAP-3.

52. The method according to item 51, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 272 to 301.

53. A method according to item 51, wherein the fragment comprises an amino acid sequence selected from any one of SEQ ID NOs: 302 to 331.

54. The method according to item 47, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, diluent, carrier, preservative or a combination thereof.

55. The pharmaceutical composition according to item 54, wherein the adjuvant is selected from the group consisting of Montanide ISA-51, QS-21, GM-CSF, cyclophosphamide, Bacillus Calmette-Guerin (BCG), Corynebacterium brevis, levamisole, azimezone, propirone, dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin (KLH), Freund's adjuvant (complete), Freund's adjuvant (incomplete), mineral gel, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, oil emulsions, dinitrophenol, diphtheria toxin (DT) and combinations thereof.

56. The method of item 47, further comprising administering to the identified subject a chemotherapeutic agent, a checkpoint inhibitor, a targeted therapy agent, a radiation therapy agent, another immunotherapeutic agent, or a combination thereof.

57. The method according to item 47, further comprising before the applying step,

A tumor sample from a subject is assayed to determine whether the three or more peptides of the pharmaceutical composition comprise two or more different amino acid sequences, each of which is

a. a fragment of a cancer associated antigen expressed by a cancer cell of the subject as determined in step (i); and

b. a T cell epitope capable of binding to at least three HLA class I molecules of a subject; and

Confirm that the subject is likely to have a clinical response to treatment.

58. A method of identifying and treating a human subject having cancer that may be immune responsive to administration of a pharmaceutical composition according to item 31, the method comprising

(i) measuring a biological sample of a subject to determine the subject's HLA genotype;

(ii) determining that the pharmaceutical composition comprises one or more sequences that are T cell epitopes capable of binding to at least three HLA class I molecules of the subject; and

(iii) administering the composition of item 31 to the identified subject.

59. A kit comprising:

A. A first pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 332 to 346; and

b. a different second pharmaceutical composition comprising one or more peptides, wherein each peptide comprises a different amino acid sequence of any one of SEQ ID NOs: 332 to 346.

60. A pharmaceutical composition comprising: a nucleic acid molecule expressing two or more polypeptides, each polypeptide comprising a fragment of up to 50 consecutive amino acids of an antigen selected from PIWIL-4, WT1, EpCAM, BORIS, AKAP-4, OY-TES-1, SP17, PIWIL-2, PIWIL-3, SPAG9, PRAME, HIWI, SURVIVIN, and AKAP-3, wherein each fragment comprises a different amino acid sequence selected from any one of SEQ ID NOs: 272 to 301.

Examples

Example 1 HLA epitope binding prediction method and validation

The prediction of binding between specific HLA and epitopes (9-mer peptides) was based on the Immune Epitope Database tool for epitope prediction (www.iedb.org).

The HLA I epitope binding prediction process was validated by comparison with HLA I epitope pairs experimentally determined in the laboratory. A dataset of HLA I epitope pairs reported in peer-reviewed publications or public immunology databases was compiled.

The consistency rate with the experimentally determined data set (Table 2) was determined. The binding HLA I epitope pairs of the data set were correctly predicted with a probability of 93%. Coincidentally, the non-binding HLA I epitope pairs were also correctly predicted with a probability of 93%.

Table 2 Analytical specificity and sensitivity of HLA epitope binding prediction methods

The accuracy of predicting multiple HLA binding epitopes was determined. Based on the analytical specificity and sensitivity using a 93% probability of true positive and true negative predictions and a 7% (=100%-93%) probability of false positive and false negative predictions, the probability of multiple HLA binding epitopes in the human body can be calculated. The probability of multiple HLA binding to epitopes shows the relationship between the number of HLA binding epitopes and the expected minimum actual binding number. According to the PEPI definition, 3 is the expected minimum number of HLA binding epitopes (bold).

Table 3 Prediction accuracy of various HLA binding epitopes

The validated HLA epitope binding prediction method was used to determine all HLA epitope binding pairs described in the Examples below.

Example 2: Multi-HLA epitope presentation predicts cytotoxic T lymphocyte (CTL) responses

It is determined that the presentation of one or more epitopes of a polypeptide antigen by one or more HLA I of an individual is predictive of a CTL response.

The study was conducted by retrospective analysis of 6 clinical trials conducted on 71 cancer and 9 HIV-infected patients (Table 4) ^1-7 . Patients from these studies were treated with HPV vaccines, three different NY-ESO-1 specific cancer vaccines, an HIV-1 vaccine, and a CTLA-4 specific monoclonal antibody, Ipilimab, which was shown to reactivate CTLs against NY-ESO-1 antigens in melanoma patients. All of these clinical trials measured antigen-specific CD8+ CTL responses (immunogenicity) in study subjects after vaccination. In some cases, correlations between CTL responses and clinical responses were reported.

No patient was excluded from the retrospective study for any reason other than data availability. The 157 patient data sets (Table 4) were randomized with a standard random number generator to create two independent cohorts for training and evaluation studies. In some cases, the cohorts included multiple data sets from the same patient, resulting in a training cohort of 76 data sets from 48 patients and a test/validation cohort of 81 data sets from 51 patients.

Table 4 Summary of patient datasets

The CTL response of the reported training data set is compared with the HLA I restriction map of vaccine antigen epitope (9-mer).Obtain each patient's antigen sequence and HLA I genotype from publicly available protein sequence databases or peer-reviewed publications, and the HLA I epitope binding prediction method is unaware of the patient's clinical CTL response data.Determine the epitope quantity of every kind of antigen that prediction is combined with at least 1 kind (PEPI1+) or at least 2 kinds (PEPI2+) or at least 3 kinds (PEPI3+) or at least 4 kinds (PEPI4+) or at least 5 kinds (PEPI5+) or all 6 kinds (PEP16+) HLA I class molecule of every patient, and the quantity combined with HLA is used as the classifier of the CTL response of report.Determine the true positive rate (sensitivity) and true negative rate (specificity) (the quantity that HLA combines) of each classifier respectively from the training data set.

ROC analysis was performed for each classifier. In the ROC curve, the true positive rate (sensitivity) of different cut-off points is plotted as a function of the false positive rate (1-specificity) (Fig. 1). Each point on the ROC curve represents the sensitivity/specificity pair corresponding to a specific decision threshold (epitope (PEPI) count). The area under the ROC curve (AUC) is a measure of the degree to which the classifier can distinguish between two diagnostic groups (CTL responders or non-responders).

This analysis unexpectedly revealed that epitope presentation predicted by multiple class I HLAs of the subject (PEPI2+, PEPI3+, PEPI4+, PEPI5+, or PEP16) in each case better predicted CTL responses than epitope presentation by only one or more HLA class I molecules (PEPI1+, AUC=0.48, Table 5).

Table 5 Diagnostic value of PEPI biomarkers determined by ROC analysis

By considering the antigenic epitopes presented by at least 3 HLA I molecules of the individual, the CTL response of the individual is best predicted (PEPI3+, AUC=0.65, Table 5). The threshold count of PEPI3+ (the number of antigen-specific epitopes presented by 3 or more HLA of the individual) for the best prediction of positive CTL response is 1 (Table 6). In other words, at least 3 HLA I molecules (≥1PEPI3+) of the subject present at least one antigen-derived epitope, and then the antigen can trigger at least one CTL clone, and the subject is a possible CTL responder. Using ≥1PEPI3+ threshold to predict possible CTL responders ("≥1PEPI3+ test") provides 76% diagnostic sensitivity (Table 12).

Table 6 Determination of ≥1 PEPI3+ threshold to predict possible CTL responders in the training dataset

Example 3 ≥1 Validation of PEPI3+ test

A test cohort of 81 data sets from 51 patients was used to validate a ≥1 PEPI3+ threshold to predict antigen-specific CTL responses. For each data set in the test cohort, it was determined whether a ≥1 PEPI3+ threshold (at least one antigen-derived epitope presented by at least three class I HLAs of the individual) was met. This was compared with the experimentally determined CTL responses reported in the clinical trial (Table 7).

Clinical validation demonstrated that PEPI3+ peptides induce CTL responses in individuals with a probability of 84%. 84% is the same value determined in the analytical validation of PEPI3+ predictions, where the epitope was predicted to bind to at least 3 HLAs of the individual (Table 3). These data provide strong evidence that PEPI induces an immune response in individuals.

Table 7 Diagnostic performance characteristics ≥1 PEPI3+ test (n=81)

ROC analysis used PEPI3+ counts as the cutoff value to determine diagnostic accuracy (Figure 2). AUC value = 0.73. For ROC analysis, an AUC of 0.7 to 0.8 is generally considered a reasonable diagnosis.

PEPI3+ counts of at least 1 (≥1 PEPI3+) best predicted CTL responses in the test dataset (Table 8). This result confirmed the thresholds determined during training (Table 5).

Table 8 Confirmation of ≥1 PEPI3+ threshold to predict likely CTL responders in the test/validation datasets.

Example 4 ≥1 PEPI3+ test predicts CD8+ CTL reactivities

The ≥1 PEPI3+ test was compared with previously reported methods for predicting CTL responses to peptide antigens in specific human subjects.

The HLA genotypes of 28 patients with cervical cancer and VIN-3 who received the HPV-16 synthetic long peptide vaccine (LPV) in two different clinical trials were determined from DNA samples ^{8 9 10} . The LPV consists of long peptides covering the HPV-16 viral oncoproteins E6 and E7. The amino acid sequence of the LPV was obtained from these publications. These publications also reported the T cell responses of each vaccinated patient to the overlapping peptide pool of the vaccine.

For each patient, LPV epitopes (9-mer) presented by at least three of the patient's class I HLAs (PEPI3+) were identified and their distribution in the peptide library was determined. Peptides containing at least one PEPI3+ (≥1 PEPI3+) were predicted to induce CTL responses. Peptides not containing PEPI3+ were predicted not to induce CTL responses.

The ≥1 PEPI3+ test correctly predicted 489 of 512 negative CTL responses and 8 of 40 positive CTL responses measured after vaccination (Figure 3A). Overall, the concordance between the ≥1 PEPI3+ test and experimentally determined CD8+ T cell reactivity was 90% (p<0.001).

For each patient, the distribution between peptide pools of epitopes presented by at least one patient class I HLA (≥1 PEPI1+, HLA-restricted epitope prediction, prior art methods) was also determined. PEPI1+ correctly predicted 116 of 512 negative CTL responses and 37 of 40 positive CTL responses measured after vaccination (Figure 3B). Overall, the concordance between HLA-restricted epitope prediction (≥1 PEPI1+) and CD8+ T cell reactivity was 28% (not significant).

Example 5 Prediction of HLA class II restricted CD4+ helper T cell epitopes

Twenty-eight cervical cancer and VIN-3 patients who received HPV-16 synthetic long peptide vaccine (LPV) in two different clinical trials (as detailed in Example 4) were studied for CD4+ helper T cell responses after LPV vaccination (Figure 4). The sensitivity of HLA class II restricted epitope prediction was 78%, as the prior art tool predicted 84 positive responses (positive CD4+ T cell reactivity to the peptide pool of human DP allele) out of 107 cases (sensitivity = 78%). The specificity was 22%, as it could exclude 7 negative responses out of 31 cases. Overall, the concordance between HLA restricted class II epitope prediction and CD4+ T cell reactivity was 66%, which was not statistically significant.

Example 6 ≥1 PEPI3+ test predicts T cell response to full-length LPV polypeptide

Using the same reported studies as in Examples 4 and 5, a ≥1 PEPI3+ test was used to predict patient CD8+ and CD4+ T cell responses to the full-length E6 and E7 polypeptide antigens of the LPV vaccine. The results were compared with experimentally determined responses. The test accurately predicted CD8+ T cell reactivity in 11 of 15 VIN-3 patients with positive CD8+ T cell reactivity test results (sensitivity 73%, PPV 85%) and 2 of 5 cervical cancer patients with CD8+ T cell reactivity (sensitivity 40%, PPV 100%). CD4+ T cell reactivity (PEPI4+) was accurately predicted to be 100% in both VIN-3 and cervical cancer patients (Figure 5).

It was also observed that class I and class II HLA restricted PEPI3+ counts were associated with clinical benefit reported in LPV vaccinated patients. Patients with higher PEPI3+ counts had complete or partial responses after 3 months.

Example 7 Case Study

pGX3001 is a DNA vaccine based on HPV16 that contains full-length E6 and E7 antigens with a linker between them. pGX3002 is a DNA vaccine based on HPV18 that contains full-length E6 and E7 antigens with a linker between them. A phase II clinical trial investigated the T cell responses of 17 HPV-infected cervical cancer patients vaccinated with pGX3001 and pGX3002 (VGX-3100 vaccination) ¹ .

Figures 5 to 6 show the location of each epitope (9-mer) presented by at least 1 (PEPI1+), at least 2 (PEPI2+), at least 3 (PEPI3+), at least 4 (PEPI4+), at least 5 (PEPI5+) or all 6 (PEP16) class I HLAs of two exemplary patients (patients 12-11 and patients 14-5) within the full-length sequences of two HPV-16 and two HPV-18 antigens.

For the combined vaccine, the total PEPI1+ count for patient 12-11 was 54 (54 epitopes presented by one or more class I HLAs), and the PEPI1+ count for patient 14-5 was 91. Therefore, for the four HPV antigens, patient 14-5 had a higher PEPI1+ count than patient 12-11. PEPI1+ represents a different vaccine antigen-specific HLA-restricted epitope set for patients 12-11 and 14-5. Only 27 PEPI1+ were common in these two patients.

For the PEPI3+ count (the number of epitopes presented by three or more of the patient's class I HLAs), the results for patients 12-11 and 14-5 were reversed. Patient 12-11 had a PEPI3+ count of 8, including at least one PEPI3+ in each of the four HPV16/18 antigens. Patient 14-5 had a PEPI3+ count of 0.

The reported immune responses for these two patients matched the PEPI3+ counts but not the PEPI1+ counts. Patients 12-11 developed an immune response to each of the four antigens after vaccination, as measured by ELISpot, while patients 14-5 did not develop an immune response to any of the four antigens of the vaccine. A similar pattern was observed when comparing the PEPI1+ and PEPI3+ groups for all 17 patients in the trial. There was no correlation between the PEPI1+ counts and experimentally measured T cell responses reported in clinical trials. However, we observed a correlation between T cell immunity predicted by ≥1 PEPI3+ tests and reported T cell immunity. ≥1 PEPI3+ tests predict immune responders to HPV DNA vaccines.

In addition, the diversity of the patient PEPI3+ groups is similar to the diversity of T cell responses typically found in cancer vaccine trials. Similar to patient 14-5, patients 12-3 and 12-6 did not have PEPI3+, which predicted that the HPV vaccine could not trigger T cell immunity. All other patients had at least one PEPI3, which predicted the possibility that the HPV vaccine could induce T cell immunity. Eleven patients had multiple PEPI3+, predicting that the HPV vaccine might trigger a polyclonal T cell response. Patients 15-2 and 15-3 produced high levels of T cell immune responses to E6 of both HPVs, but had poor immune responses to E7. Other patients 15-1 and 12-11 had the same degree of response to E7 of HPV18 and HPV16, respectively.

Example 8 Designing model populations for in silico experiments and identifying candidate precision vaccine targets in large populations

A computer simulation human test group of 433 subjects has a complete 4-bit HLA I class genotype (2×HLA-A*xx:xx; 2×HLA-B*xx:xx; 2×HLA-C*xx:xx) and compiled demographic information. The model population has a total of 152 different HLA alleles, representing> 85% of the currently known allele G group.

A "large population" database containing 7189 subjects was also established, which was characterized by 4 HLA genotypes and demographic information. The large population had 328 different HLA class I alleles. The HLA allele distribution of the model population was significantly correlated with the large population (Table 9) (Pearson p < 0.001). Therefore, the 433 patient model population represents a 16-fold larger population.

The model population represents 85% of the human population in terms of HLA diversity and HLA frequency.

Table 9 Statistical analysis of HLA distribution in the “model population” and “large population”

Example 9: In silico experiments based on identification of multiple HLA binding epitopes predicted T cell response rates in reported clinical trials

The aim of this study was to determine whether a model population, such as that described in Example 8, could be used to predict CTL reactivity rates of a vaccine, ie, for use in in silico efficacy trials.

Twelve peptide vaccines derived from cancer antigens were identified from peer-reviewed publications that induced T cell responses in a subset of subjects. These peptides have been studied in clinical trials that have recruited a total of 172 patients. T cell responses induced by the vaccine peptides have been determined and reported from blood samples. The immune response rate was determined as the percentage of study subjects with a positive T cell response measured in the clinical trial (Figure 7).

Table 10 Clinical trials with peptide vaccines

Peptide vaccines Source antigen Peptide length T cell assay Group (n) References MMNLMQPKTQQTYTYD JUP 16-mer Polymer staining 18 12 GRGSTTTNYLLDRDDYRNTSD ADA17 21-mer Polymer staining 18 12 LKKGAADGGKLDGNAKLNRSLK BAP31 22-mer Polymer staining 18 12 FPPKDDHTLKFLYDDNQRPYPP top2A 22-mer Polymer staining 18 12 RYRKPDYTLDDGHGLLRFKST Abl-2 21-mer Polymer staining 18 12 QRPPFSQLHRFLADALNT DDR1 18-mer Polymer staining 18 12 ALDQCKTSCALMQQHYDQTSCFSSP ITGB8 25-mer Polymer staining 18 12 STAPPAHGVTSAPDTRPAPGSTAPP MUC-1 25-mer proliferation 80 13 YLEPGPVTA gp100 9-mer Tetramer 18 14 MTPGTQSPFFLLLLLTVLTVV MUC-1 21-mer Cytotoxicity 10 15 SSKALQRPV Bcr-Abl 9-mer ELISPOT 4 16 RMFPNAPYL WT-1 9-mer Polymer staining twenty four 17 RMFPNAPYL(HLA-A*0201) WT-1 9-mer Cytokine staining 18 18

In each of the 433 subjects in the model population described in Example 8, 12 peptides were studied with ≥1 PEPI3+ tests. The "≥1 PEPI3+ score" for each peptide was calculated as the proportion of subjects in the model population with at least one vaccine-derived epitope that can bind to at least three subject-specific HLA class I molecules (≥1 PEPI3+). If the corresponding clinical trial stratifies patients in the HLA allele selection population, the model population is also screened for subjects with the corresponding allele (examples: WT1, HLA-A*0201).

The experimentally determined trial reported response rates were compared to a ≥1 PEPI3+ score. The overall percentage of agreement (OPA) was calculated from the paired data (Table 11). A linear correlation was observed between a ≥1 PEPI3+ score and response rate (R ² =0.77) ( FIG. 7 ). This result suggests that the identification of peptides that are predicted to bind to multiple HLAs of an individual can be used to predict the outcome of an in silico clinical trial.

Table 11 Comparison of PEPI3+ scores and CTL response rates of 12 peptide vaccines

*Percentage of subjects in the model population with ≥1 vaccine-derived PEPI3+

Example 10 Prediction of T cell response rates reported in Clinical Trial II based on computer simulation experiments identifying multiple HLA binding epitopes

Nineteen clinical trials with published immune response rates (IRRs) for peptide- or DNA-based vaccines were identified (Table 12). These trials involved 604 patients and covered 38 vaccines derived from tumor and viral antigens. Vaccine antigen-specific CTL responses were measured in each study patient, and response rates in the clinical study population were calculated and reported.

Each vaccine peptide from the 19 clinical trials was tested with ≥1 PEPI3+ in each subject of the model population. The ≥1 PEPI3+ score for each peptide was calculated as the proportion of subjects in the model population with at least one vaccine-derived PEPI3+. As described in Example 9, the experimentally determined test reported response rates were compared with the PEPI scores (Table 13). A linear correlation was observed between the response rate and the ≥1 PEPI3+ score (R ² =0.70) (Figure 8). This result confirms that the identification of peptides that are predicted to bind to multiple HLAs of an individual can predict the T cell response of a subject, and that computer simulation experiments can predict the results of clinical trials.

Table 12 Response rates published in clinical trials

Table 13 There is a linear correlation between PEPI score and response rate (R ² = 0.7)

*Percentage of subjects in the model population with ≥1 vaccine-derived PEPI3+

Example 11 In silico simulations based on identification of multiple HLA binding epitopes in peptide vaccines predict reported clinical trial immune response rates

IMA901 is a therapeutic vaccine for renal cell carcinoma (RCC) containing 9 peptides derived from tumor-associated peptides (TUMAPs) that are naturally present in human cancer tissues. In two independent clinical studies (Phase I and Phase II), a total of 96 HLA-A*02+ subjects with advanced RCC were treated with IMA901. Each of the 9 peptides of IMA901 has been identified as an HLA-A2 restricted epitope in the prior art. Based on currently recognized standards, they are all strong candidate peptides for promoting T cell responses against renal cancer in test subjects, because their presence has been detected in renal cancer patients, and because test patients are specifically selected to have at least one HLA molecule capable of presenting each peptide.

For each subject in the model population, how many of the nine peptides of the IMA901 vaccine can bind to three or more HLAs were determined. Since each peptide in the IMA901 vaccine is a 9-mer, this corresponds to the PEPI3+ count. The results are compared with the immune response rates reported in Phase I and Phase II clinical trials (Table 14).

Table 14 Immune response rate of IMA901 in the model population and two clinical trials

*Patients whose immune response was not assessed

Results from phase I and II studies have shown variability in immune responses to the same vaccine in different trial cohorts. However, overall, there was good agreement between response rates predicted by ≥2 PEPI3+ tests and reported clinical response rates.

In a retrospective analysis, clinical investigators of the above trial found that subjects who responded to multiple peptides of the IMA901 vaccine were significantly (p=0.019) more likely to experience disease control (stable disease, partial response) than subjects who responded to only one peptide or no response. Six of the eight subjects (75%) who responded to multiple peptides experienced clinical benefit in the trial, compared to 14% and 33% of 0 and 1 peptide responders, respectively. Randomized Phase II trials have confirmed that immune responses to multiple TUMAPs are associated with longer overall survival.

Since the presentation of PEPI accurately predicts the responders of TUMAP, the clinical responders of IMA901 are likely to be patients who can present ≥2 PEPIs from TUMAP. This subgroup accounts for only 27% of HLA-A*02 selected patients, and according to the clinical trial results, it is expected that 75% of this subgroup will experience clinical benefits. The same clinical results show that if patient selection is based on ≥3 PEPIs from TUMAP, 100% of patients will experience clinical benefits, although this group will only represent 3% of the patient population selected by HLA-A*02. These results show that in the patient population studied in the IMA901 clinical trial, the disease control rate (stable disease or partial response) is between 3% and 27%. In the absence of a complete response, only a portion of these patients can experience survival benefits.

These findings explain the lack of improved survival in the Phase III IMA901 clinical trial. These results also suggest that HLA-A*02 enrichment of the study population was insufficient to achieve the primary overall survival endpoint in the Phase III IMA901 trial. As noted by the IMA901 trial investigators, a companion diagnostic (CDx) needs to be developed to select possible responders to peptide vaccines. These findings also suggest that selecting patients with ≥2 TUMAP-specific PEPIs may provide sufficient enrichment to demonstrate significant clinical benefit of IMA901.

Example 12 In silico experiments based on identification of vaccine-derived multi-HLA binding epitopes predict reported experimental clinical response rates

The correlation between the ≥2PPI3+ score of the immunotherapy vaccine determined in the model population described in Example 8 and the reported disease control rate (DCR, proportion of patients with complete response and partial response and stable disease) determined in clinical trials was determined.

Seventeen clinical trials with peptide- and DNA-based cancer immunotherapy vaccines were found in peer-reviewed scientific journals that have published disease control rates (DCR) or objective response rates (ORR) (Table 15). These trials involved 594 patients and covered 29 tumors and viral antigens. DCR was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST), which is the current standard for clinical trials, in which clinical responses are based on changes in the largest cross-sectional ^{dimensions42,43,44} . In the absence of available DCR data, objective response rate (ORR) data, also defined according to the RECIST guidelines, were used.

Table 16 compares the ≥2PPI3+ score for each vaccine in the model population and published DCR or ORR. A correlation between predicted and measured DCR was observed, providing further evidence that not only immunogenicity but also cancer vaccine efficacy depends on individual HLA sequences ( ^R2 = 0.76) (Figure 9).

Table 15 Clinical trials selected for disease control rate (DCR) prediction

Table 16 Disease control rate (DCR) and MultiPEPI score (predicted DCR) in 17 clinical trials

Example 13 Breast cancer vaccine design for large populations and compositions

Taking into account the heterogeneity of tumor antigens and patient HLA, we used the above-mentioned PEPI3+ test to design peptides for breast cancer vaccines that were effective in a large proportion of patients.

As reported in peer-reviewed publications, breast cancer CTA is identified and graded based on the overall expression frequency of antigens found in breast cancer tumor specimens (Chen et al. Multiple Cancer/Testis Antigens ArePreferentially Expressed in Hormone-Receptor Negative and High-Grade Breast Cancers. Plos One 2011;6(3):e17876.; Kanojia et al. Sperm-Associated Antigen 9, a Novel Biomarker for Early Detection of Breast Cancer. Cancer Epidemiol Biomarkers Prev 2009;18(2):630–639.; Saini et al. A Novel Cancer Testis Antigen, A-Kinase Anchor Protein 4 (AKAP4) Is a Potential Biomarker for Breast Cancer. Plos One 2013;8(2):e57095).

Based on the graded expression rates, we selected the CTA with the highest expression frequency as the target antigen for breast cancer vaccine. The expression rates of the selected breast cancer-specific CTAs are shown in FIG11 .

To select immunogenic peptides from target CTAs, we used the PEPI3+ test and the model population described in Example 8 to identify 9-mer epitopes (PEPI3+s) that are most commonly presented by at least 3 HLAs of individuals in the model population. We refer to these epitopes as "bestEPIs" herein. Figure 10 shows an illustrative example of "PEPI3+ hotspot" analysis and bestEPI identification of the PRAME antigen.

We multiplied the frequency of expression of each CTA reported by the frequency of PEPI3+ hot spots in the model population to identify T cell epitopes (9-mers) that will induce immune responses against breast cancer antigens in the highest proportion of individuals (Table 17). Then we selected 15-mers (Table 17) containing each selected 9-mer. Using the method described in Example 19 below, 15-mers were selected to bind to most HLA class II alleles of most subjects. These 15-mers can induce CTL and helper T cell responses in the highest proportion of subjects.

Table 17 BestEPI list for selecting breast cancer peptides for vaccine composition (underlined 9-mer). N%: frequency of antigen expression in colorectal cancer; B%: BestEPI frequency, i.e., the percentage of individuals with epitopes that bind at least 3 HLA I class molecules of the subject in the model population (433 subjects); HLA II**: the percentage of individuals with CD4+T cell-specific PEPI4+ in normal donors (n=400); N%*B%: N% multiplied by B%.

Then we designed 31 kinds of 30-mer peptides (Table 18a). Each 30-mer is composed of two optimized 15-mer fragments, usually from CTAs of different frequencies, wherein the 15-mer fragments are arranged end to end, and each fragment contains one of the 9-mers (BestEPI) in Table 17. Nine of these 30-mer peptides are selected as a group of peptides, referred to as PolyPEPI915 (Table 18b). Figure 11 shows the expression frequency of 10 CTAs targeted by PolyPEPI915 in single and combined forms.

Table 18a 30-mer breast cancer vaccine peptides

Table 18b Selected breast cancer vaccine peptides for PolyPEPI915 group/composition

*Percentage of individuals with CD8+ T cell-specific PEPI3+ in the model population (n=433).

**Percentage of individuals with CD4+ T cell-specific PEPI4+ in normal donors (n=433).

Characterization of PolyPEPI915

Tumor heterogeneity can be addressed by including peptide sequences of multiple CTAs in targeted vaccines or immunotherapy regimens. The PolyPEPI915 composition targets 10 different CTAs. Based on the antigen expression rates of these 10 CTAs, we simulated the predicted average number of expressed antigens in cancer cells (AG50) and the minimum number of expressed antigens with 95% probability (AG95). 95% of individuals express at least 4 of the 10 target antigens (AG95=4), as shown in the antigen expression curve in Figure 12.

The above AG values characterize vaccines that are independent of the target patient population. They can be used to predict the likelihood that a specific cancer (e.g., breast cancer) expresses an antigen targeted by a specific vaccine or immunotherapy composition. AG values are based on known tumor heterogeneity but do not take into account HLA heterogeneity.

The HLA heterogeneity of certain populations can be characterized from the perspective of immunotherapy or vaccine compositions by the number of antigens representing PEPI3+. These are vaccine-specific CTA antigens predicted to be ≥1 PEPI3+, referred to herein as "AP". The average number of antigens with PEPI3+ (AP50) shows how the vaccine induces an immune response to the antigens targeted by the composition (breast cancer vaccine-specific immune response). The PolyPEPI915 composition can induce an immune response to an average of 5.3 vaccine antigens (AP50 = 5.30), and 95% of the model population can induce an immune response to at least one vaccine antigen (AP95 = 1) (Figure 13).

The vaccine can be further characterized by the AGP value, which refers to the antigen with PEPI. This parameter is a combination of the previous two parameters: (1) AG depends on the frequency of antigen expression in a specific tumor type, but not on the HLA genotype of individuals in the population, and (2) AP depends on the HLA genotype of individuals in the population, regardless of the frequency of antigen expression. AGP depends on the expression frequency of the vaccine antigen in the disease and the HLA genotype of individuals in the population.

Combining the data of breast cancer AG and AP in the model population, we determined the AGP value of PolyPEPI915, which represents the probability distribution of vaccine antigens that induce immune responses to antigens expressed in breast tumors. For PolyPEPI915, the AGP50 value in the model population was 3.37. AGP92 = 1, meaning that 92% of the subjects in the model population induced an immune response to at least one expressed vaccine antigen (Figure 14).

Example 14 Patient Selection Using Companion Diagnostics for Breast Cancer Vaccines

The likelihood that a particular patient will have an immune response or clinical response to treatment with, for example, one or more cancer vaccine peptides as described above can be determined based on (i) identification of PEPI3+ within the vaccine peptide (a 9-mer epitope capable of binding to at least three HLAs of the patient); and/or (ii) determination of target antigen expression in the patient's cancer cells, for example as measured in a tumor biopsy. Ideally, both parameters are determined and the best combination of vaccine peptides is selected for treating the patient. However, if, for example, determination of expressed tumor antigens by biopsy is not possible, not recommended, or is unreliable due to biopsy error (i.e., a biopsy tissue sample obtained from a small portion or metastatic tumor does not represent the entire repertoire of CTAs expressed in the patient), PEPI3+ analysis alone can be used.

Example 15 Comparison of PolyPEPI915 with competing breast cancer vaccines

We used the in silico clinical trial model described above to predict immune response rates for competing breast cancer vaccines that have been studied in clinical trials (Table 19). Immune response rates ranged from 3% to 91%.

Single peptide vaccines were immunogenic in 3% to 23% of individuals. In contrast, peptides with amino acid sequences selected from SEQ ID No: 81 to 111 were immunogenic in 44% to 73% of individuals in the same cohort. This result represents a significant improvement in the immunogenicity of each peptide in PolyPEPI915.

The immune response rates of the competing combination peptide products ranged from 10% to 62%. The PolyPEPI915 combination product of the present invention was 96% in the model population and 93% in the breast cancer patient population, representing an improvement in immunogenicity.

Table 19 Predicted immune response rates of competing breast cancer vaccines

*Proportion of subjects with ≥1 PEPI3+

Another improvement using the PolyPEPI915 vaccine is the lower chance of tumor escape. Each 30-mer peptide in PolyPEPI915 targets 2 tumor antigens. CTLs targeting more tumor antigens are more effective against heterologous tumor cells than CTLs targeting a single tumor antigen.

Another improvement is that the PolyPEPI915 vaccine is that individuals who may respond to vaccination can use the methods described herein to identify based on their HLA genotype (sequence) and optionally the antigen expression in their tumor. Pharmaceutical compositions containing the PolyPEPI vaccine will not be applied to such individuals, whose HLA cannot present any PEPI3 from the vaccine. During clinical trials, the number of mAGP or AGP in the PolyPEPI915 scheme is related to the duration of individual responses. It is most likely necessary to have a vaccine combination of>1AGP to destroy heterologous tumor cells. Pharmaceutical compositions containing PolyPEPI will not be applied to individuals whose HLA cannot present any PEPI3 from the vaccine.

Example 16 Colorectal cancer vaccine design and composition

We show another example of a colorectal vaccine composition using the same design approach described above. Taking into account the heterogeneity of tumor antigens and patient HLA, we used the above PEPI3+ test to design peptides for colorectal cancer vaccines that were effective in a large proportion of patients.

As reported in peer-reviewed publications, colorectal cancer CTA identifies and stratifies tumors based on the overall expression frequency of antigens found in colorectal cancer tumor specimens ( FIG. 19 ). (Choi J, Chang H. The expression of MAGE and SSX, and correlation of COX2, VEGF, and survivin in colorectalcancer. Anticancer Res 2012.32(2):559-564.; Goossens-Beumer IJ, Zeestraten EC, Benard A, Christen T, Reimers MS, Keijzer R, Sier CF, Liefers GJ, Morreau H, PutterH, Vahr meijer AL, van de Velde CJ, KuppenPJ. Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectalcancer. Br JCancer 2014.110(12):2935-2944.; Li M, Yuan YH, Han Y, Liu YX, Yan L, Wang Y, Gu J. Expression profile of cancer-testis genes in 121human colorectalcancer tissue and adjacent normal tissue. Clinical Cancer Res 2005.11(5):1809–1814).

Based on the graded expression rates, we selected the CTA with the highest expression frequency as the target antigen for the colorectal cancer vaccine. The expression rates of the selected breast cancer-specific CTAs are shown in FIG15 .

To select immunogenic peptides from the most frequently expressed colorectal cancer CTAs, we used the PEPI3+ assay and the model population described in Example 8 to identify the “bestEPI”.

We multiplied the reported expression frequency of each CTA (N%) by the frequency of PEPI3+ hotspots in the model population (B%) to identify T cell epitopes (9-mers) that would induce immune responses against colorectal cancer antigens in the highest proportion of individuals (Table 20). We then selected 15-mers that included each selected 9-mer (Table 20). Using the methods described in Example 19 below, 15-mers were selected to bind to the majority of HLA class II alleles in the majority of subjects. These 15-mers can induce CTL and helper T cell responses in the highest proportion of subjects.

Table 20 BestEPI list for selecting colorectal cancer peptides for vaccine composition (9-mers are underlined). N%: frequency of antigen expression in colorectal cancer; B%: BestEPI frequency, i.e., the percentage of individuals with epitopes that bind at least 3 HLA class I molecules of the subject in the model population (433 subjects); HLAII**: the percentage of individuals with CD4+ T cell-specific PEPI4+ in normal donors (n=400); N%*B%: N% multiplied by B%.

Then we designed 31 kinds of 30-mer peptides (Table 21a). Each 30-mer is composed of two optimized 15-mer fragments, usually from CTAs of different frequencies, and each 30-mer usually contains at least one high-frequency HLA class II binding PEPI. The 15-mer fragments are arranged end to end, and each fragment contains one of the 9-mers (BestEPI) in the above Table 20. Nine of these 30-mer peptides are selected as a group of peptides, which are called PolyPEPI915 (Table 21b). Figure 15 shows the expression frequency of 8 kinds of CTAs targeted by PolyPEPI915 in single and combined forms.

Table 21a 30-mer colorectal cancer vaccine peptides

*Percentage of individuals with CD8+ T cell-specific PEPI3+ in the model population (n=433).

**Percentage of individuals with CD4+ T cell-specific PEPI4+ in normal donors (n=433).

Table 21b Selected colorectal cancer vaccine peptides for use in PolyPEPI915 compositions

*Percentage of individuals with CD8+ T cell-specific PEPI3+ in the model population (n=433).

**Percentage of individuals with CD4+ T cell-specific PEPI4+ in normal donors (n=433).

Characterization of PolyPEP1015 Colorectal Cancer Vaccine

Tumor heterogeneity: The PolyPEP1015 composition targets 8 different CTAs (Figure 15). Based on the antigen expression rates of these 8 CTAs, AG50 = 5.22 and AG95 = 3 (Figure 16). Patient heterogeneity: AP50 = 4.73 and AP95 = 2 (AP95 = 2) (Figure 17). Tumor and patient heterogeneity: AGP50 = 3.16 and AGP95 = 1 (model population) (Figure 18).

Example 17 Comparison of colorectal cancer vaccine peptides with competing colorectal cancer vaccines

We used the above-mentioned computer simulation clinical trial model to determine the T cell responder ratio of the CRC peptide vaccine of the prior art and the current development, and compared it with polyPEP1015 (Table 22). Our PEPI3+ test proved that the competitive vaccine can induce an immune response to one tumor antigen in a portion of subjects (2% to 77%). However, the multi-antigen (multi-PEPI) response determination for 2 competitive multi-antigen vaccines resulted in no or 2% responders. * In the case of 1 or 2, 3, 4 or 5 antigens of the vaccine composition, the percentage of responders is the ratio of subjects from the 1≥PEPI3+ model population with HLAI (CD8+T cell response). Since multi-PEPI responses are associated with clinical responses induced by tumor vaccines, it is unlikely that any competitive vaccine will show clinical benefits in 98% of patients. On the contrary, we predict multi-PEPI responses in 95% of subjects, indicating the possibility of clinical benefits in most patients.

Table 22 Predicted immune response rates of PolyPEP1015 and competing colorectal cancer vaccines

Example 18 Ovarian cancer vaccine design and composition

Using essentially the same design approach as described in Examples 13 and 16 above, we designed ovarian cancer vaccine peptides using the PEPI3+ test.

We multiplied the frequency of expression of the reported CTAs associated with ovarian cancer (N%) by the frequency of PEPI3+ hotspots in the model population (B%) to identify T cell epitopes (9-mers) that would induce an immune response against ovarian cancer antigens in the highest proportion of individuals (Table 23). We then selected 15-mers that included each selected 9-mer (Table 23). Using the method described in Example 20 below, 15-mers were selected to bind to most HLA class II alleles in most subjects.

Table 23 BestEPI list for selecting ovarian cancer peptides for vaccine composition (9-mers are underlined). N%: frequency of antigen expression in colorectal cancer; B%: BestEPI frequency, i.e., the percentage of individuals with epitopes that bind at least 3 HLA class I molecules of the subject in the model population (433 subjects); HLAII**: the percentage of individuals with CD4+T cell-specific PEPI4+ in normal donors (n=400); N%*B%: N% multiplied by B%.

We then designed 15 30-mer peptides (Table 24).

Table 24 30-mer ovarian cancer vaccine peptides

*Percentage of individuals with CD8+ T cell-specific PEPI3+ in the model population (n=433).

**Percentage of individuals with CD4+ T cell-specific PEPI4+ in normal donors (n=400).

Example 19 Efficacy of the Design Approach Illustrated by the PolyPEP1018 Colorectal Cancer Vaccine

The PolyPEP1018 colorectal cancer (CRC) vaccine (PolyPEP1018) composition is a peptide vaccine intended for use as an additional immunotherapy to the standard of care CRC treatment option for patients identified as possible responders using a companion in vitro diagnostic test (CDx). Clinical trials are ongoing in the United States and Italy to evaluate PolyPEP1018 in patients with metastatic colorectal cancer. The product contains 6 peptides (6 of the 30-mer peptide PolyPEP1015 described in Examples 16 and 17) mixed with the adjuvant Montanide. These 6 peptides were selected to induce T cell responses against 12 epitopes of 7 cancer testis antigens (CTAs) most commonly expressed in CRC. These 6 peptides were optimized to induce persistent CRC-specific T cell responses. Companion diagnostics (CDx) can be used to select possible responding patients with T cell responses against multiple CTAs expressed in tumors. This example illustrates the precise process used to design PolyPEP1018. This method can be used to design vaccines for other cancers and diseases.

A. Selection of multi-antigen targets

The selection of tumor antigens is essential for the safety and efficacy of cancer vaccines. The characteristic of a good antigen is limited expression in normal tissues, thereby preventing autoimmunity. Several classes of antigens meet this requirement, including uniquely mutated antigens (e.g., p53), viral antigens (e.g., human papillomavirus antigens in cervical cancer), and differentiation antigens (e.g., CD20 expressed in B-cell lymphomas).

The inventors selected a variety of cancer testis antigens (CTAs) as target antigens because they are expressed in various types of tumor cells and testicular cells, but not in any other normal somatic tissues or cells. CTAs are ideal targets for vaccines for at least the following reasons:

Tumors with higher histological grade and later clinical stage often show higher CTA expression frequency

Only a subset of tumor cells express a certain CTA

Different cancer types show significant differences in CTA expression frequencies

Tumors that are positive for CTA often show simultaneous expression of more than one CTA

None of the CTAs appear to be cell surface antigens, so they are unique targets for cancer vaccines (they are not suitable targets for antibody-based immunotherapies)

In order to identify the target CTA of PolyPEP1018, the inventors constructed a CTA expression knowledge base. The knowledge base contains CTAs represented by CRCs graded by expression rate. Related studies conducted by the inventors (see Example 11) show that vaccines that induce CTL responses against multiple antigens expressed in tumor cells can benefit patients. Therefore, 7 CTAs with high expression rates in CRC were selected for inclusion in the development of PolyPEP1018. Details are listed in Table 25.

Table 25 Target CTAs in PolyPEP1018 CRC vaccine

B. Precise targeting through vaccine design based on PEPI3+ biomarkers

As described above, the PEPI3+ biomarker predicts the vaccine-induced T cell response of the subject. The inventors have developed and validated a test for accurately identifying PEPIs from antigen sequences and HLA genotypes (Examples 1, 2, 3). The PEPI test algorithm is used to identify the best PEPI (bestEPI) from the 7 target CTAs included in the PolyPEP1018 CRC vaccine.

The dominant PEPIs identified using the methods described herein induced CTL responses in the highest proportion of subjects:

i. Identify all HLA class I binding PEPIs from 7 CTA targets in each of the 433 subjects in the model population;

ii. Identification of the dominant PEPIs (BestEPIs), which are the PEPIs present in the largest subpopulation.

Table 26 gives 12 dominant PEPIs derived from 7 CTAs in polyPEP1018. The PEPI% in the model population represents the proportion of 433 subjects with the indicated PEPI, i.e., the proportion of subjects in which the indicated PEPI can induce a CTL response. Although optimization steps were used during the identification process, there was a very high variability (18%-78%) in the dominant PEPIs that induced CTL responses.

Table 26 Advantages of CRC-specific HLA class I binding in PolyPEP1018

The inventors optimized each dominant PEPI to bind to the majority of HLA class II alleles in most subjects. This should enhance efficacy because it will induce CD4+ helper T cells, which can enhance CD8+ CTL responses and contribute to long-term sustained T cell responses. The example shown in Figure 4 demonstrates that PEPIs that bind ≥3 HLA class II alleles are most likely to activate helper T cells.

The 15-mer peptides selected using the methods described herein contain dominant PEPIs for HLA class I and class II binding. Therefore, these peptides can induce CTL and helper T cell responses in the highest proportion of subjects.

process:

1. Identify the HLA class II genotypes of 400 normal donors*;

2. Extend each 9-mer dominant PEPI on both sides with amino acids matching the source antigen (Table 20);

3. IEDB algorithm predicted HLA class II PEPI in 400 normal donors;

4. Select the subject 15-mer peptide with the highest proportion of HLA class II binding PEPIs;

5. When linking two 15-mer peptides, ensure that there is one dominant HLA class II PEPI in each vaccine peptide.

Table 27 shows 12 optimized 15-mer peptides derived from 7 CTAs in PolyPEP1018. These peptides have different HLA class II binding characteristics. Despite this optimized personalized vaccine design, there is high variability (0% to 100%) in the PEPI generation ability (≥3 HLA binding) among these peptides.

Table 27 Antigen-specific HLA class II binding to PEPI in PolyPEP1018

Compared with shorter peptides, 30-mer vaccine peptides have the following advantages:

(i) Multiple precisely selected tumor-specific immunogens: Each 30-mer contains two precisely selected cancer-specific immunogenic peptides that are capable of inducing CTL and helper T cell responses in the most relevant population (similar to the model population).

(ii) Ensuring native antigen presentation: Peptides as long as 30-mer can be considered as prodrugs: they are not biologically active themselves, but are processed into smaller peptides (9 to 15 amino acids long) in order to be loaded into the HLA molecules of specialized antigen-presenting cells. Antigen presentation resulting from long peptide vaccination reflects the physiological pathway of presentation in HLA class I and class II molecules. In addition, long peptide processing in cells is more efficient than processing of large intact proteins.

(iii) Elimination of induction of tolerance T cell responses: 9-mer peptides do not need to be processed by professional antigen presenting cells and thus bind exogenously to HLA class I molecules. Therefore, injected short peptides will bind in large quantities to HLA class I molecules on all nucleated cells with surface HLA class I. In contrast, peptides >20-mer long are processed by antigen presenting cells before binding to HLA class I. Therefore, vaccination with long peptides is less likely to lead to tolerance and will promote the desired anti-tumor activity.

(iv) Induces long-lasting T cell responses because it can stimulate helper T cell responses by binding to a variety of HLA class II molecules

(v) Practicality: GMP production, formulation, quality control and administration of a smaller number of peptides, each with all of the above characteristics, is more feasible than a larger number of peptides providing different characteristics.

Each 30-mer peptide in PolyPEP1018 consists of 2 HLA class I binding dominant PEPIs and at least one HLA class II strongly binding PEPI. Strong binding PEPIs bind to 4 HLA class II alleles in >50% of individuals. Therefore, the vaccine peptides are suitable for HLA class I and class II alleles of individual subjects in the general population (which is the relevant population for CRC vaccine design).

As described above, the high variability of HLA genotypes in subjects leads to high variability in T cell responses induced by PolyPEP1018. This proves that the co-development of CDx to determine possible responders is reasonable. PEP13+ and >2PEP13+ biomarkers can predict the immune response and clinical response of subjects vaccinated with PolyPEP1018 as described in Examples 11 and 12, respectively. These biomarkers will be used to co-develop CDx to predict possible responders to the PolyPEP1018 CRC vaccine.

Example 20 Analysis of the composition and immunogenicity of PolyPEP1018 CRC vaccine

The peptides selected for the PolyPEP1018 composition are shown in Table 28.

Table 28 Selected colorectal cancer vaccine peptides for PolyPEP1018 composition

*Percentage of individuals with HLA class I binding PEPI3+ in the model population (n=433).

**Percentage of individuals with HLA class II binding PEPI3+ in the model population (n=433).

The peptides of PolyPEPI1018 are formulated into two mixtures, namely, MIX 1 containing the peptides of SEQ IDs: 1 30 and 131 and MIX 2 containing the peptides of SEQ IDs: 121, 124, 134 and 126. MIX 1 and MIX 2 may be administered sequentially.

Immunogenicity characterization

The inventors used the PEPI3+ test to characterize the immunogenicity of PolyPEPI018 in a cohort of 37 CRC patients with complete HLA genotype data. T cell responses to the same 9-mer peptides that will be used in clinical trials were predicted in each patient. These peptides represent 12 dominant PEP13+ in the PolyPEP1018 peptide. The 9-mer is shown in Table 26.

The specificity and sensitivity of PEPI3+ prediction depends on the actual number of HLAs predicted to bind to a specific epitope. Specifically, the inventors have determined that the probability of an HLA-restricted epitope inducing a T cell response in a subject is typically 4%, which explains the low sensitivity of the prior art prediction methods based on HLA-restricted epitope predictions. Applying the PEPI3+ method, the inventors determined the probability of PolyPEPI018 inducing T cells to respond specifically to each dominant PEPI3+ in 37 CRC patients. The results of this analysis are summarized in Table 29.

Table 29 Probability of dominant PEPIs among the six peptides of PolyPEP1018 in 37 CRC patients

Abbreviations: CRC = colorectal cancer; PEPI = personal epitope

Note: The percentage represents the probability of PolyPEPI1018-induced CD8+ T cell response.

In summary, these results indicate that the most immunogenic peptide in PolyPEP1018 is CRC-P8, which is predicted to bind >3HLA in most patients. The least immunogenic peptide CRC-P3 binds to >1HLA in many patients and has a 22% chance of inducing a T cell response. Since the bioassays used to detect T cell responses are not as accurate as PEPI3+, this calculation may be the most accurate characterization of T cell responses in CRC patients. Although MAGE-A8 and SPAG9 are immunogenic in the model population used for vaccine design, there is no MAGE-A8-specific PEPI3+ in 37 CRC patients, and only 1 patient (3%) has SPAG9-specific PEPI3+.

Tables 30 and 31 show further characterization of the predicted PolyPEP1018 response rates in the model population described in Example 8 and in 295 CRC patients with known HLA class I genotypes.

Table 30 PolyPEP1018 response rates in the model population (433 normal donors).

Table 31 Response rate of PolyPEPI1018 in 295 CRC patients

Toxicity characterization - immunoBLAST

A method has been developed that can be performed on any antigen to determine its potential to induce a toxic immune response such as autoimmunity. The method is referred to herein as immunoBLAST. PolyPEP1018 contains 6 30-mer polypeptides. Each polypeptide consists of two 15-mer peptide fragments derived from an antigen expressed in CRC. New epitopes may be generated in the connecting region of the two 15-mer peptides and may induce an undesirable T cell response (autoimmunity) against healthy cells. This was assessed using the immunoBLAST method applied by the inventors.

16-mer peptides were designed for each 30-mer component of PolyPEP1018. Each 16-mer contains 8 amino acids from the end of the first 15 residues of the 30-mer and 8 amino acids from the start of the second 15 residues of the 30-mer, thus accurately spanning the connecting region of the two 15-mers. These 16-mers were then analyzed using BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) to identify cross-reactive regions of local similarity with human sequences, which compares protein sequences to sequence databases and calculates the statistical significance of matches. 8-mers in the 16-mer were selected as the detection length because this length represents the minimum length required for a peptide to form an epitope and is the distance between anchor points during HLA binding.

As shown in Figure 19, the positions of amino acids in the polypeptide are numbered. The starting position of the potential 9-mer peptide that can bind to HLA and form a new epitope is 8 amino acids at positions 8–15. The starting position of the tumor antigen-derived peptide carried by the 15-mer that can form a drug-active epitope is 7+7=14 amino acids at positions 1–7 and 16–22. The proportion of potential new epitope-generating peptides is 36.4% (8/22).

The PEP13+ test is used to identify new epitopes and neoPEP1 in the 9-mer epitope of the connecting region. The risk of PolyPEP1018 inducing unwanted T cell responses was assessed in 433 subjects in the model population by determining the proportion of subjects with PEP1I3+ in the 9-mer of the connecting region. The results of the new epitope/neoPEPI analysis are summarized in Table 32. Among the 433 subjects in the model population, the average number of predicted epitopes that can be produced by intracellular processing is 40.12. New epitopes are often generated; 11.61 (28.9%) of the 40.12 epitopes are new epitopes. Most peptides can be identified as new epitopes, but the number of subjects presenting new epitopes is different.

The epitopes carried by PolyPEP1018 produced an average of 5.21PEP13+. These PEPIs can activate T cells in subjects. The amount of potential new PEPIs is much lower than that of new epitopes (3.7%). In some subjects, these neoPEPIs are unlikely to compete with PEPIs for T cell activation. Importantly, the activated neoPEPI-specific T cells have no targets on healthy tissues.

Table 32 Identification of potential new epitopes of PolyPEP1018

Abbreviations: CRC = colorectal cancer; HLA = human leukocyte antigen; PEPI = personal epitope

Each of the 30-mer peptides in PolyPEP1018 was released for clinical development because none of the 8-mers in the linker region matched any human protein other than the target CTA.

Activity/Efficacy Characterization

The inventors have developed pharmacodynamic biomarkers to predict the activity/efficacy of vaccines in individual human subjects as well as in populations of human subjects. These biomarkers accelerate the development of more effective vaccines and also reduce development costs. The inventors have the following tools:

Antigen Expression Knowledge Base: The inventors have collected data from experiments published in peer-reviewed scientific journals on tumor antigens expressed by tumor cells and organized by tumor type to create a database of CTA expression levels - the CTA Database (CTADB). As of April 2017, CTADB contains data from 145 CTAs from 41,132 tumor samples and is organized by the frequency of CTA expression in different types of cancer.

Computer simulation test population: The inventors also collected data on HLA genotypes of several different model populations. Each individual in the population has complete 4-digit HLA genotype data. The population is summarized in Table 33.

Table 33 Computer simulation test population

Abbreviations: CRC = colorectal cancer; HLA = human leukocyte antigen

Using these tools (or perhaps equivalent databases or model populations), the following markers can be assessed:

AG95 - Vaccine efficacy: The number of antigens expressed with 95% probability by a specific tumor type in a cancer vaccine. AG95 is an indicator of vaccine efficacy and is independent of the immunogenicity of the vaccine antigens. AG95 is calculated based on tumor antigen expression rate data collected in the CTADB. Technically, AG95 is determined by the binomial distribution of the CTA, taking into account all possible variations and expression rates. In this study, AG95 is calculated by accumulating the probability of a certain number of expressed antigens with the widest range of antigens, where the sum of probabilities is less than or equal to 95%. The correct value is between 0 (95% probability of no expression expected) and the maximum number of antigens (95% probability of all antigens expressed).

· PEPI3+ count - Immunogenicity of the vaccine in the subject: Vaccine-derived PEPI3+ is a personal epitope that induces a T cell response in the subject. PEPI3+ can be determined using the PEPI3+ test in subjects with a known full 4-digit HLA genotype.

AP count - antigenicity of the vaccine in the subject: the number of vaccine antigens with PEPI3+. Vaccines such as PolyPEP1018 contain sequences from antigens expressed in tumor cells. The AP count is the number of antigens in the vaccine that contain PEPI3+. The AP count represents the number of antigens in the vaccine that can induce a T cell response in the subject. The AP count characterizes the vaccine-antigen-specific T cell response of the subject because it depends only on the HLA genotype of the subject and is independent of the subject's disease, age, and drug treatment. The correct value is between 0 (no antigen presents PEPI) and the maximum number of antigens (all antigens present PEPI).

AP50 - Antigenicity of the vaccine in a population: The average number of vaccine antigens with PEPI in a population. AP50 is suitable for characterizing vaccine-antigen-specific T cell responses in a given population because it depends on the HLA genotype of the subjects in the population. Technically, AP counts are calculated in the model population and the binomial distribution of the results is used to calculate AP50.

AGP count - Efficacy of the vaccine in the subject: the number of vaccine antigens expressed in the tumor with PEPIs. The AGP count represents the number of tumor antigens that the vaccine recognized and induced a T cell response (hit the target). The AGP count depends on the vaccine-antigen expression rate in the subject's tumor and the subject's HLA genotype. The correct value is between 0 (no PEPI expressing antigen presentation) and the maximum number of antigens (all antigens are expressed and present PEPIs).

·AGP50 - cancer vaccine efficacy in a population: the average number of vaccine antigens expressed in a specified tumor with PEPI (ie, AGP) in a population. AGP50 represents the average number of tumor antigens that can be identified by a vaccine-induced T cell response. AGP50 depends on the expression rate of the antigen in the tumor type shown and the immunogenicity of the antigen in the target population. AGP50 can evaluate the efficacy of vaccines in different populations and can be used to compare different vaccines in the same population. The calculation of AGP50 is similar to that for AG50, except that expression is weighted by the appearance of PEPI3+ on the vaccine antigen expressed in the subject. In a theoretical population where each subject has a PEPI from each vaccine antigen, AGP50 will be equal to AG50. In another theoretical population, where no subject has a PEPI from any vaccine antigen, AGP50 will be 0. In general, the following statements are valid: 0≤AGP50≤AG50.

mAGP - Candidate biomarker for selecting likely responders: The probability that a cancer vaccine induces a T cell response against multiple antigens expressed in a given tumor. mAGP is calculated by the expression rate of vaccine-antigens in CRC and the presentation rate of vaccine-derived PEPI in subjects. Technically, mAGP is the sum of the probabilities of multiple AGPs (>2 AGPs) based on the AGP distribution.

Application of these markers to assess antigenicity and efficacy in individual CRC patients

Table 34 shows the antigenicity and efficacy of PolyPEP1018 in 37 CRC patients using AP and AGP50, respectively. As expected from the high variability of PolyPEP1018-specific T cell responses (see Table 29), AP and AGP50 have high variability. The most immunogenic antigen in PolyPEP1018 is FOXO39; every patient has PEPI3+. However, FOXO39 is only expressed in 39% of CRC tumors, indicating that 61% of patients will have FOXO39-specific T cell responses that do not recognize tumors. The weakest immunogenic antigen is MAGE-A8; although the antigen is expressed in 44% of CRC tumors, none of the 37 CRC patients had PEPI3+. These results indicate that antigen expression and immunogenicity can be considered when determining the efficacy of cancer vaccines.

AGP50 represents the average number of antigens expressed in CRC tumors with PEPI. Patients with higher AGP50 values are more likely to respond to PolyPEP1018, as higher AGP50 values indicate that the vaccine can induce T cell responses against more antigens expressed in CRC cells.

The last column in Table 34 shows the probability of mAGP (multiple AGPs; i.e., at least 2 AGPs) in each of the 37 CRC patients. The average mAGP in CRC patients was 66%, indicating that the probability of CRC patients inducing T cell responses against multiple antigens expressed in tumors was 66%.

Table 34 Antigenicity (AP counts), potency (AGP50 counts) and mAGP of PolyPEP1018 in 37 CRC patients

Abbreviations: CRC = colorectal cancer; PEPI = personal epitope; CTA = cancer testis antigen; AP = expressed antigen with ≥1 PEPI

These biomarkers have immediate utility in vaccine development and routine clinical practice as they do not require invasive biopsies. Antigen expression data can be obtained from obtained tumor samples and organized in a database. 4-digit HLA genotyping can be performed from saliva samples. It is a validated test for transplantation and paternity testing performed by certified laboratories worldwide. These assessments will allow drug developers and physicians to gain greater insight into the immunogenicity and activity of tumor responses and the potential emergence of resistance.

Application of these markers to assess antigenicity and efficacy of PolyPEPI1018 in populations

Antigenicity of PolyPEP1018 CRC vaccine in the general population

The antigenicity of PolyPEP1018 in the subjects was determined by AP counts, which indicate the number of vaccine antigens that induced a T cell response in the subjects. The AP count of PolyPEP1018 was determined in each of the 433 subjects in the model population using the PEPI test, and then the AP50 count of the model population was calculated.

As shown in Figure 20, the AP50 of PolyPEP1018 in the model population is 3.62. Therefore, the average number of immunogenic antigens (i.e., antigens with ≥1 PEPI) in PolyPEP1018 in the general population is 3.62.

Efficacy of PolyPEP1018 CRC vaccine in the general population

If the PEPI in the vaccine is presented by tumor cells, the vaccine-induced T cells can recognize and kill tumor cells. The number of AGPs (expressed antigens with PEPIs) is an indicator of vaccine efficacy in an individual and depends on the efficacy and antigenicity of PolyPEP1018. As shown in Figure 21, in the model population, the average number of immunogenic CTAs (i.e., APs [expressed antigens with ≥1 PEPIs]) in PolyPEP1018 was 2.54.

The probability of PolyPEP1018 inducing T cell responses against multiple antigens (i.e. mAGP) in subjects in the model population was 77%. Comparison of PolyPEP1018 CRC vaccine activity in different populations

Table 35 shows the comparison of immunogenicity, antigenicity and efficacy of PolyPEP1018 in different populations.

Table 35 Comparison of immunogenicity, antigenicity and efficacy of PolyPEP1018 in different subpopulations

Abbreviations: CRC = colorectal cancer; PEPI = personal epitope; SD = standard deviation; AP = expressed antigen with ≥1 PEPI

The average of PEPI3+ and AP results showed that PolyPEPI018 was highly immunogenic and antigenic in all populations; PolyPEP1018 induced an average of 3.7–6.0 CRC-specific T cell clones against 2.9–3.7 CRC antigens. PolyPEP1018 immunogenicity was similar in CRC patients and the average population (p>0.05), and this similarity may be due to the small sample size of the CRC population.

Example 21 Personalized immunotherapy composition for treating ovarian cancer

This example describes the treatment of ovarian cancer patients with personalized immunotherapy compositions, wherein the compositions are specifically designed for the patients based on their HLA genotypes based on the disclosures described herein. This example and Example 22 below provide clinical data to support the principle of inducing cytotoxic T cell responses on multiple HLA binding epitopes in a subject, based on the disclosures described herein.

The HLA class I and class II genotypes of patient XYZ with metastatic ovarian adenocarcinoma were determined from a saliva sample.

In order to prepare a personalized pharmaceutical composition for patient XYZ, 13 peptides were selected, each of which met the following two criteria: (i) derived from an antigen expressed in ovarian cancer, as reported in a peer-reviewed scientific publication; and (ii) comprising a fragment of a T cell epitope capable of binding at least three HLA class I molecules of patient XYZ (Table 36). In addition, each peptide was optimized to bind the maximum number of HLA class II molecules of the patient.

Table 36 Personalized vaccine for ovarian cancer patient XYZ

Vaccine for XYZ Target Antigen Antigen expression 20-mer peptide Maximum number of HLAI classes Maximum number of HLA class II POC01_P1 AKAP4 89% NSLQKQLQAVLQWIAASQFN 3 5 POC01_P2 BORIS 82% SGDERSDEIVLTVSNSNVEE 4 2 POC01_P3 SPAG9 76% VQKEDGRVQAFGWSLPQKYK 3 3 POC01_P4 OY-TES-1 75% EVESTPMIMENIQELIRSAQ 3 4 POC01_P5 SP17 69% AYFESLLEKREKTNFDPAEW 3 1 POC01_P6 WT1 63% PSQASSGQARMFPNAPYLPS 4 1 POC01_P7 HIWI 63% RRSIAGFVASINEGMTRWFS 3 4 POC01_P8 PRAME 60% MQDIKMILKMVQLDSIEDLE 3 4 POC01_P9 AKAP-3 58% ANSVVSDMMVSIMKTLKIQV 3 4 POC01_P10 MAGE-A4 37% REALSNKVDELAHFLLRKYR 3 2 POC01_P11 MAGE-A9 37% ETSYEKVINYLVMLNAREPI 3 4 POC01_P12a MAGE-A10 52% DVKEVDPTGHSFVLVTSLGL 3 4 POC01_P12b BAGE 30% SAQLLQARLMKEESPVVSWR 3 2

According to the validation of the PEPI test shown in Table 3, the 11 PEPI3 peptides in the immunotherapy composition can induce T cell responses in XYZ with a probability of 84%, and two PEPI4 peptides (POC01-P2 and POC01-P5) induce T cell responses with a probability of 98%. T cell responses target 13 antigens expressed in ovarian cancer. The expression of these cancer antigens in patient XYZ was not tested. Instead, the probability of successful killing of cancer cells was determined based on the probability of antigen expression in the patient's cancer cells and the positive predictive value of ≥1 PEPI3+ test (AGP count). The AGP count predicts the effectiveness of the vaccine in the subject: the number of vaccine antigens expressed in the patient's tumor (ovarian adenocarcinoma) with PEPI. The AGP count represents the number of tumor antigens that the vaccine identifies and induces a T cell response (hitting the target) against the patient's tumor. The AGP count depends on the vaccine-antigen expression rate in the subject's tumor and the subject's HLA genotype. The correct value must be between 0 (no expression of antigen-presenting PEPI) and the maximum number of antigens (all antigens are expressed and present PEPI).

The probability that patient XYZ will express one or more of the 12 antigens is shown in Figure 22. AGP95=5, AGP50=7.9, mAGP=100%, AP=13.

The pharmaceutical composition for patient XYZ can be composed of at least 2 of the 13 peptides (Table 36), because it is determined that presenting at least two polypeptide fragments (epitopes) that can bind to at least three HLAs (≥2 PEPI3+) of an individual in a vaccine or immunotherapy composition can predict clinical response. The above peptides are synthesized and dissolved in a pharmaceutically acceptable solvent and mixed with an adjuvant before injection. It is desirable that the patient receive personalized immunotherapy with at least two peptide vaccines, but it is more preferred to increase the likelihood of killing cancer cells and reduce the chance of recurrence.

To treat patient XYZ, 12 peptides were formulated into 4 x 3/4 peptides (POC01/1, POC01/2, POC01/3, POC01/4). One treatment cycle was defined as administration of all 13 peptides within 30 days.

Patient history:

Diagnosis: Metastatic ovarian adenocarcinoma

Age: 51

Family history: Colon and ovarian cancer (mother); breast cancer (grandmother)

Tumor pathology: BRCA1-185delAG, BRAF-D594Y, MAP2K1-P293S, NOTCH1-S2450N

2011: First diagnosis of ovarian adenocarcinoma; Wertheim procedure and chemotherapy; lymph node dissection

2015: Pericardial fat tissue transfer, resection

2016: Liver metastases

2017: Retroperitoneal and mesenteric lymphadenopathy; early peritoneal cancer with a small amount of ascites

Previous treatment:

2012: Paclitaxel-Carboplatin (6×)

2014: Kailai-Carboplatin (1×)

2016-2017 (9 months): Lymparza (olaparib) 2 x 400 mg/day, oral

2017: Hycamtin infusion 5 x 2.5 mg (3x a series/month)

PIT vaccine treatment started on April 21, 2017.

Table 37 Patient XYZ peptide treatment regimen

Patients' tumor MRI findings (baseline April 15, 2016):

Disease is primarily confined to the liver and lymph nodes. Use of MRI limits detection of metastases to the lungs (pulmonary)

May 2016 to January 2017: Olaparib treatment

December 25, 2016 (before PIT vaccine treatment): Significant reduction in tumor burden with confirmation of the response obtained at FU2

January to March 2017 - TOPO (topoisomerase)

April 6, 2017: FU3 demonstrated regrowth of existing lesions and appearance of new lesions leading to disease progression

·PIT started on April 21, 2017

July 21, 2017 (after the second cycle of PIT): FU4 showed continued growth of the lesion, general enlargement of the pancreas, abnormal parapancreatic signals, and increased ascites

July 26, 2017 – CBP + Gem + Avastin

On September 20, 2017 (after 3 cycles of PIT), FU5 showed reversal of lesion growth and improved pancreatic/parapancreatic signals. The results suggest pseudoprogression

On November 28, 2017 (after 4 cycles of PIT), FU6 showed the best response with elimination of non-target lesions

The MRI data of patient XYZ are shown in Table 38 and Figure 23.

Table 38 Summary of lesion responses

Example 22 Design of personalized immunotherapy composition for treating breast cancer

Determine the HLA I class and II class genotype of metastatic breast cancer patient ABC from saliva sample.In order to prepare the personalized pharmaceutical composition for patient ABC, select 12 kinds of peptides, each peptide meets the following two standards: (i) derived from the antigen expressed in breast cancer, as reported in peer-reviewed scientific publications; (ii) comprise the fragment (table 39) of the T cell epitope of at least three kinds of HLA I class molecules that can be combined with patient ABC.In addition, optimize each peptide to combine the HLA II class of the maximum number of patients.These 12 kinds of peptides target 12 kinds of breast cancer antigens.The probability of one or more of patient ABC expressing 12 kinds of antigens is as shown in Figure 24.

Table 39: 12 peptides for the treatment of breast cancer patients

BRC09 vaccine peptides Target Antigen Antigen expression 20-mer peptide Maximum number of HLAI classes Maximum number of HLA class II PBRC01_cP1 FSIP1 49% ISDTKDYFMSKTLGIGRLKR 3 6 PBRC01_cP2 SPAG9 88% FDRNTESLFEELSSAGSGLI 3 2 PBRC01_cP3 AKAP4 85% SQKMDMSNIVLMLIQKLLNE 3 6 PBRC01_cP4 BORIS 71% SAVFHERYALIQHQKTHKNE 3 6 PBRC01_cP5 MAGE-A11 59% DVKEVDPTSHSYVLVTSLNL 3 4 PBRC01_cP6 NY-SAR-35 49% ENAHGQSLEEDSALEALLNF 3 2 PBRC01_cP7 HOM-TES-85 47% MASFRKLTLSEKVPPNHPSR 3 5 PBRC01_cP8 NY-BR-1 47% KRASQYSGQLKVLIAENTML 3 6 PBRC01_cP9 MAGE-A9 44% VDPAQLEFMFQEALKLKVAE 3 8 PBRC01_cP10 SCP-1 38% EYEREETRQVYMDLNNNIEK 3 3 PBRC01_cP11 MAGE-A1 37% PEIFGKASESLQLVFGIDVK 3 3 PBRC01_cP12 MAGE-C2 twenty one% DSESSFTYTLDEKVAELVEF 4 2

Predicted efficacy: AGP95 = 4; the probability that the PIT vaccine induces a CTL response against the four CTAs expressed in BRC09 breast cancer cells is 95%. Other efficacy parameters: AGP50 = 6.3, mAGP = 100%, AP = 12.

Efficacy detected after the first vaccination with all 12 peptides: 83% reduction in tumor metabolic activity (PET CT data).

To treat patient ABC, the 12 peptides were formulated into 4 x 3 peptides (PBR01/1, PBR 01/2, PBR 01/3, PBR01/4). One treatment cycle was defined as administration of all 12 different peptide vaccines within 30 days.

Patient history:

Diagnosis: Bilateral metastatic breast cancer: the right breast is ER positive, PR negative, and Her2 negative; the left breast is ER, PR, and Her2 negative.

First diagnosis: 2013 (4 years before PIT vaccine treatment)

2016: Extensive metastatic disease with involvement of supra- and infra-diaphragmatic lymph nodes. Multiple liver and lung metastases.

2016–2017 Treatment: Etrozole, Ibance, and Zoladex

result:

March 7, 2017: Previous PIT vaccine treatment

Multifocal metastatic disease of the liver with true external compression of the common bile duct origin and massive dilatation of the intrahepatic bile ducts. Abdominal, hilar, and retroperitoneal adenopathy

May 26, 2017: 1 PIT cycle later

Efficacy tested: 8 tumor metabolic activity (PET CT) liver, lung lymph nodes and other metastases decreased by 3%. Safety tested: Skin reactions

Local inflammation at the injection site within 48 hours after vaccine administration

Follow-up:

BRC-09 was treated with 5 cycles of PIT vaccine. She felt well and she refused a PET CT scan in September 2017. She became symptomatic in November and a PET CT scan showed progressive disease, but she refused all treatment. In addition, her oncologist found that she had stopped taking Pablocyclib since the spring and summer. Patient ABC died in January 2018.

The combination of Pablocyclib and personalized vaccines may be responsible for the significant early responses observed after vaccine administration. Palbocyclib has been shown to improve the activity of immunotherapy by increasing CTA presentation of HLAs and reducing the proliferation of Tregs: (Goel et al. Nature. 2017: 471-475). PIT vaccines can be used as an add-on to existing technology treatments to achieve maximum efficacy.

Example 23 Personalized immunotherapy composition for treating patients with advanced metastatic breast cancer

Patient BRC05 was diagnosed with right-sided inflammatory breast cancer with extensive lymphangiogenic carcinoma. Inflammatory breast cancer (IBC) is a rare but aggressive form of locally advanced breast cancer. It is called inflammatory breast cancer because its main symptoms are swelling and redness (the breast often looks inflamed). Most inflammatory breast cancers are invasive ductal carcinomas (starting in the milk ducts). This type of breast cancer is associated with the expression of oncoproteins of high-risk human papillomaviruses. In fact, HPV16 DNA was diagnosed in this patient's tumor.

Patient phase 2011 (6 years before PIT vaccine treatment)

T4: Tumor of any size that extends directly to the chest wall and/or skin (ulcer or skin nodule)

pN3a: metastasis to ≥10 axillary lymph nodes (at least 1 tumor deposit ≥2.0 mm); or metastasis to the subclavian (level III axillary lymph node) nodes.

14 vaccine peptides were designed and prepared for patient BRC05 (Table 40). Peptides PBRC05-P01-P10 were prepared for this patient based on population expression data. The last 3 peptides in Table 40 (SSX-2, MORC, MAGE-B1) were designed from antigens whose expression was measured directly in the patient's tumor.

Table 40 Vaccine peptides of patient BRC05

BRC05 vaccine peptide Target Antigen Antigen expression 20-mer peptide HLAI class maximum HLA class II maximum PBRC05_P1 SPAG9 88% XXXXXXXXXXXXXXXXXXXXX 3 4 PBRC05_P2 AKAP4 85% XXXXXXXXXXXXXXXXXXXXX 3 4 PBRC05_P3 MAGE-A11 59% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P4 NY-SAR-35 49% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P5 FSIP1 49% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P6 NY-BR-1 47% XXXXXXXXXXXXXXXXXXXXX 3 4 PBRC05_P7 MAGE-A9 44% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P8 SCP-1 38% XXXXXXXXXXXXXXXXXXXXX 3 6 PBRC05_P9 MAGE-A1 37% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P10 MAGE-C2 twenty one% XXXXXXXXXXXXXXXXXXXXX 3 3 PBRC05_P11 MAGE-A12 13% XXXXXXXXXXXXXXXXXXXXX 3 4 PBRC05_P12 SSX-2 6% XXXXXXXXXXXXXXXXXXXXX 3 1 PBRC05_P13 MORC ND XXXXXXXXXXXXXXXXXXXXX 3 4 PBRC05_P14 MAGE-B1 ND XXXXXXXXXXXXXXXXXXXXX 3 3

Note: Bold red indicates CD8 PEPI and underlined indicates the best binding CD4 allele.

T cell responses were detected in peripheral mononuclear cells 2 weeks after the first immunization with the mixture of peptides PBRC05_P1, PBRC05_P2, PBRC05_P3, PBRC05_P4, PBRC05_P5, PBRC05_P6, PBRC05_P7.

Table 41 Antigen-specific T cell responses: number of spots/300,000 PBMCs

antigen Stimulants Experience 1 Experience 2 average value SPAG9 PBRC05_P1 2 1 1.5 AKAP4 PBRC05_P2 11 4 7.5 MAGE-A11 PBRC05_P3 26 32 29 NY-SAR-35 PBRC05_P4 472 497 484.5 FSIP1 PBRC05_P5 317 321 319 NY-BR-1 PBRC05_P6 8 12 10 MAGE-A9 PBRC05_P7 twenty three 27 25 none Negative control (DMSO) 0 3 1.5

The results showed that a single immunization with 7 peptides induced effective T cell responses against 3 of the 7 peptides, demonstrating effective MAGE-A11, NY-SAR-35, FSIP1, and MAGE-A9 specific T cell responses. There were weak responses to AKAP4 and NY-BR-1, and no response to SPAG9.

References

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⁵ Yuan et al. Integrated NY-ESO-1antibody and CD8+T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci US A. 2011;108(40):16723-16728.

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¹³ Butts et al. Randomized phase IIB trial of BLP25 liposome vaccine instage IIIB and IV non-small-cell lung cancer. JClin Oncol. 2005; 23(27):6674-81.

¹⁴ Yuan et al. Safety and immunogenicity of a human and mouse gp100 DNAvaccine in a phase I trial of patients with melanoma. Cancer Immun. 2009; 9:5.

¹⁵ Kovjazin et al. ImMucin: a novel therapeutic vaccine with promiscuousMHC binding for the treatment of MUC1-expressing tumors. Vaccine. 2011; 29(29-30):4676-86.

¹⁶ Cathcart et al. Amultivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood. 2004; 103:1037-1042.

¹⁷ Chapuis et al.Transferred WT1-reactive CD8+T cells can mediateantileukemic activity and persist in post-transplant patients.Sci TranslMed.2013;5(174):174ra27.

¹⁸ Keilholz et al. Aclinical and immunologic phase 2trial of Wilms tumorgene product 1(WT1)peptide vaccination in patients with AML and MDS. Blood; 2009; 113(26):6541-8.

¹⁹ Walter et al.Multipeptide immune response to cancer vaccine IMA901after single-dose cyclophosphamide associates with longer patientssurvival.Nat Med.2012;18(8):1254-61.

²⁰ Phuphanich et al. Phase I trial of a multi-epitope-pulsed dendriticcell vaccine for patients with newly diagnosed glioblastoma. Cancer ImmunolImmunother. 2013;62(1):125-35.

²¹ Kantoff et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010; 28(7):1099-105.

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²⁵ Fenoglio et al. Amulti-peptide,dual-adjuvant telomerase vaccine(GX301) is highly immunogenic in patients with prostate and renalcancer. Cancer Immunol Immunother; 2013;62:1041–1052.

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Sequence Listing

<110> TREOS BIO ZRT

<120> Vaccines

<130> N409651WO

<150> EP 17159242.1

<151> 2017-03-03

<150> GB 1703809.2

<151> 2017-03-09

<150> EP 17159243.9

<151> 2017-03-03

<160> 449

<170> PatentIn version 3.5

<210> 1

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 1

<400> 1

Tyr Leu Met Asn Arg Pro Gln Asn Leu

1 5

<210> 2

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 2

<400> 2

Met Met Ala Tyr Ser Asp Thr Thr Met

1 5

<210> 3

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 3

<400> 3

Phe Thr Ser Ser Arg Met Ser Ser Phe

1 5

<210> 4

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 4

<400> 4

Tyr Ala Leu Gly Phe Gln His Ala Leu

1 5

<210> 5

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 5

<400> 5

Lys Met Ser Ser Leu Leu Pro Thr Met

1 5

<210> 6

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 6

<400> 6

Phe Thr Val Cys Asn Ser His Val Leu

1 5

<210> 7

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 8

<400> 7

Met Ala Phe Val Thr Ser Gly Glu Leu

1 5

<210> 8

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 8

<400> 8

Tyr Leu His Ala Arg Leu Arg Glu Leu

1 5

<210> 9

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 9

<400> 9

Val Met Ser Glu Arg Val Ser Gly Leu

1 5

<210> 10

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 10

<400> 10

Phe Thr Gln Ser Gly Thr Met Lys Ile

1 5

<210> 11

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 11

<400> 11

Phe Ser Ser Ser Gly Thr Thr Ser Phe

1 5

<210> 12

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 12

<400> 12

Phe Met Phe Gln Glu Ala Leu Lys Leu

1 5

<210> 13

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 13

<400> 13

Phe Val Leu Ala Asn Gly His Ile Leu

1 5

<210> 14

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 15

<400> 14

Lys Ala Met Val Gln Ala Trp Pro Phe

1 5

<210> 15

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 15

<400> 15

Tyr Ser Cys Asp Ser Arg Ser Leu Phe

1 5

<210> 16

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 16

<400> 16

Arg Ala Ile Glu Gln Leu Ala Ala Met

1 5

<210> 17

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 17

<400> 17

Ala Met Asp Ala Ile Phe Gly Ser Leu

1 5

<210> 18

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 18

<400> 18

Met Ala Ser Phe Arg Lys Leu Thr Leu

1 5

<210> 19

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 19

<400> 19

Ser Ser Ile Ser Val Tyr Tyr Thr Leu

1 5

<210> 20

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 20

<400> 20

Ser Ala Phe Glu Pro Ala Thr Glu Met

1 5

<210> 21

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 21

<400> 21

Phe Ser Tyr Glu Gln Asp Pro Thr Leu

1 5

<210> 22

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 22

<400> 22

Arg Thr Tyr Trp Ile Ile Ile Glu Leu

1 5

<210> 23

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 23

<400> 23

Thr Thr Met Glu Thr Gln Phe Pro Val

1 5

<210> 24

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 24

<400> 24

Phe Ser Phe Val Arg Ile Thr Ala Leu

1 5

<210> 25

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 25

<400> 25

Lys Met Ser Ser Leu Leu Pro Thr Met

1 5

<210> 26

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 26

<400> 26

Lys Met His Ser Leu Leu Ala Leu Met

1 5

<210> 27

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 27

<400> 27

Phe Met Asn Pro Tyr Asn Ala Val Leu

1 5

<210> 28

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 28

<400> 28

Lys Ser Met Thr Met Met Pro Ala Leu

1 5

<210> 29

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 29

<400> 29

Tyr Val Asp Glu Lys Ala Pro Glu Phe

1 5

<210> 30

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 30

<400> 30

Lys Thr Met Ser Thr Phe His Asn Leu

1 5

<210> 31

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 31

<400> 31

Arg Ala Ile Glu Gln Leu Ala Ala Met

1 5

<210> 32

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 32

<400> 32

Val Met Ser Glu Arg Val Ser Gly Leu

1 5

<210> 33

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 33

<400> 33

Tyr Arg Ala Gln Arg Phe Trp Ser Trp

1 5

<210> 34

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 34

<400> 34

Phe Phe Phe Glu Arg Ile Met Lys Tyr

1 5

<210> 35

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 35

<400> 35

Ser Thr Phe Lys Asn Trp Pro Phe Leu

1 5

<210> 36

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 36

<400> 36

Ala Ile Trp Glu Ala Leu Ser Val Met

1 5

<210> 37

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 37

<400> 37

Lys Val Ala Glu Leu Val Arg Phe Leu

1 5

<210> 38

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 38

<400> 38

Phe Val Gln Glu Asn Tyr Leu Glu Tyr

1 5

<210> 39

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 39

<400> 39

Arg Ala Leu Ala Glu Thr Ser Tyr Val

1 5

<210> 40

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 40

<400> 40

Tyr Ile Phe Ala Thr Cys Leu Gly Leu

1 5

<210> 41

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 1

<400> 41

Asp Gln Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu

1 5 10 15

<210> 42

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 2

<400> 42

Met Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp

1 5 10 15

<210> 43

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 3

<400> 43

Met Phe Thr Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His Met Lys

1 5 10 15

<210> 44

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 4

<400> 44

Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro Ser

1 5 10 15

<210> 45

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 5

<400> 45

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala

1 5 10 15

<210> 46

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 6

<400> 46

Gly Asn Ile Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu

1 5 10 15

<210> 47

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 7

<400> 47

Asn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg

1 5 10 15

<210> 48

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 8

<400> 48

Leu Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu

1 5 10 15

<210> 49

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 9

<400> 49

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

1 5 10 15

<210> 50

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 10

<400> 50

His Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu

1 5 10 15

<210> 51

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 11

<400> 51

Phe Ser Ser Ser Gly Thr Thr Ser Phe Lys Cys Phe Ala Pro Phe

1 5 10 15

<210> 52

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 12

<400> 52

Gln Leu Glu Phe Met Phe Gln Glu Ala Leu Lys Leu Lys Val Ala

1 5 10 15

<210> 53

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 13

<400> 53

Cys Ser Gly Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu

1 5 10 15

<210> 54

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 14

<400> 54

Arg His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe

1 5 10 15

<210> 55

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 15

<400> 55

Tyr Ser Cys Asp Ser Arg Ser Leu Phe Glu Ser Ser Ala Lys Ile

1 5 10 15

<210> 56

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 16

<400> 56

Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met

1 5 10 15

<210> 57

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 17

<400> 57

Ser Pro Thr Ala Met Asp Ala Ile Phe Gly Ser Leu Ser Asp Glu

1 5 10 15

<210> 58

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 18

<400> 58

Met Ala Ser Phe Arg Lys Leu Thr Leu Ser Glu Lys Val Pro Pro

1 5 10 15

<210> 59

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 19

<400> 59

Ser Ser Ile Ser Val Tyr Tyr Thr Leu Trp Ser Gln Phe Asp Glu

1 5 10 15

<210> 60

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 20

<400> 60

Pro Gly Lys Pro Ser Ala Phe Glu Pro Ala Thr Glu Met Gln Lys

1 5 10 15

<210> 61

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 21

<400> 61

Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg Asp

1 5 10 15

<210> 62

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 22

<400> 62

Val Arg Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg

1 5 10 15

<210> 63

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 23

<400> 63

Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly Lys

1 5 10 15

<210> 64

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 24

<400> 64

Gly Thr Gly Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu

1 5 10 15

<210> 65

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 25

<400> 65

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala

1 5 10 15

<210> 66

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 26

<400> 66

Leu Ala Ser Lys Met His Ser Leu Leu Ala Leu Met Val Gly Leu

1 5 10 15

<210> 67

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 27

<400> 67

Lys Phe Met Asn Pro Tyr Asn Ala Val Leu Thr Lys Lys Phe Gln

1 5 10 15

<210> 68

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 68

<400> 68

Pro Lys Ser Met Thr Met Met Pro Ala Leu Phe Lys Glu Asn Arg

1 5 10 15

<210> 69

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 29

<400> 69

Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser Met Gln Gly Leu Lys

1 5 10 15

<210> 70

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 30

<400> 70

Phe Lys Lys Thr Met Ser Thr Phe His Asn Leu Val Ser Leu Asn

1 5 10 15

<210> 71

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 31

<400> 71

Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met

1 5 10 15

<210> 72

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 32

<400> 72

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

1 5 10 15

<210> 73

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 33

<400> 73

Ser Arg Tyr Arg Ala Gln Arg Phe Trp Ser Trp Val Gly Gln Ala

1 5 10 15

<210> 74

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 34

<400> 74

Lys Val Asn Phe Phe Phe Glu Arg Ile Met Lys Tyr Glu Arg Leu

1 5 10 15

<210> 75

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 35

<400> 75

Lys Asp His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu

1 5 10 15

<210> 76

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 36

<400> 76

Ser Arg Ala Pro Glu Glu Ala Ile Trp Glu Ala Leu Ser Val Met

1 5 10 15

<210> 77

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 37

<400> 77

Asp Glu Lys Val Ala Glu Leu Val Arg Phe Leu Leu Arg Lys Tyr

1 5 10 15

<210> 78

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 38

<400> 78

Gln Tyr Phe Val Gln Glu Asn Tyr Leu Glu Tyr Arg Gln Val Pro

1 5 10 15

<210> 79

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 39

<400> 79

Glu Phe Leu Trp Gly Pro Arg Ala Leu Ala Glu Thr Ser Tyr Val

1 5 10 15

<210> 80

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 80

<400> 80

Ile Gly His Val Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr

1 5 10 15

<210> 81

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 1

<400> 81

Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro Ser Met

1 5 10 15

Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp

20 25 30

<210> 82

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 2

<400> 82

Val Cys Met Phe Thr Ser Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His Val

1 5 10 15

Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg Leu

20 25 30

<210> 83

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 3

<400> 83

Asn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg His

1 5 10 15

Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu

20 25 30

<210> 84

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 4

<400> 84

Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala Lys

1 5 10 15

Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser

20 25 30

<210> 85

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 5

<400> 85

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala Met

1 5 10 15

Met Gln Met Phe Gly Leu Gly Ala Ile Ser Leu Ile Leu Val

20 25 30

<210> 86

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 6

<400> 86

Leu Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu Gln

1 5 10 15

Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys Leu

20 25 30

<210> 87

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 7

<400> 87

Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Leu

1 5 10 15

Arg His Lys Cys Cys Phe Ser Ser Ser Gly Thr Thr Ser Phe

20 25 30

<210> 88

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 8

<400> 88

Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Gln

1 5 10 15

Leu Glu Phe Met Phe Gln Glu Ala Leu Lys Leu Lys Val Ala

20 25 30

<210> 89

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 9

<400> 89

Thr Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr Tyr

1 5 10 15

Ser Cys Asp Ser Arg Ser Leu Phe Glu Ser Ser Ala Lys Ile

20 25 30

<210> 90

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 10

<400> 90

Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala Val

1 5 10 15

Cys Met Phe Thr Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His

20 25 30

<210> 91

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 11

<400> 91

Leu Arg His Lys Cys Cys Phe Ser Ser Ser Gly Thr Thr Ser Phe Gln

1 5 10 15

Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys Leu

20 25 30

<210> 92

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 12

<400> 92

Tyr Ser Cys Asp Ser Arg Ser Leu Phe Glu Ser Ser Ala Lys Ile Thr

1 5 10 15

Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met

20 25 30

<210> 93

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 13

<400> 93

Met Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp His

1 5 10 15

Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu

20 25 30

<210> 94

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 14

<400> 94

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala Leu

1 5 10 15

Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro Ser

20 25 30

<210> 95

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 15

<400> 95

Thr Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr Asn

1 5 10 15

Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg

20 25 30

<210> 96

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 16

<400> 96

Met Met Gln Met Phe Gly Leu Gly Ala Ile Ser Leu Ile Leu Val Val

1 5 10 15

Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg Leu

20 25 30

<210> 97

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer peptide 17

<400> 97

Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Lys

1 5 10 15

Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser

20 25 30

<210> 98

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 18

<400> 98

Leu Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu Gln

1 5 10 15

Leu Glu Phe Met Phe Gln Glu Ala Leu Lys Leu Lys Val Ala

20 25 30

<210> 99

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 19

<400> 99

Gly Asn Ile Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Leu

1 5 10 15

Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro Ser

20 25 30

<210> 100

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 20

<400> 100

Asn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg Phe

1 5 10 15

Ser Ser Ser Gly Thr Thr Ser Phe Lys Cys Phe Ala Pro Phe

20 25 30

<210> 101

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 21

<400> 101

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala Met

1 5 10 15

Phe Thr Ser Ser Arg Met Ser Ser Phe Asn Arg His Met Lys

20 25 30

<210> 102

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 22

<400> 102

Thr Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr His

1 5 10 15

Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr

20 25 30

<210> 103

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 23

<400> 103

Met Ala Ser Phe Arg Lys Leu Thr Leu Ser Glu Lys Val Pro Pro Ser

1 5 10 15

Pro Thr Ala Met Asp Ala Ile Phe Gly Ser Leu Ser Asp Glu

20 25 30

<210> 104

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 24

<400> 104

Asp Gln Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg

1 5 10 15

His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe

20 25 30

<210> 105

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 25

<400> 105

Cys Ser Gly Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu Ser

1 5 10 15

Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

20 25 30

<210> 106

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast Vaccine 26

<400> 106

Asp Leu Ser Phe Tyr Val Asn Arg Leu Ser Ser Leu Val Ile Gln Ser

1 5 10 15

Ser Ile Ser Val Tyr Tyr Tyr Thr Leu Trp Ser Gln Phe Asp Glu

20 25 30

<210> 107

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 27

<400> 107

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser Ser

1 5 10 15

Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe Ala Thr Pro

20 25 30

<210> 108

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 28

<400> 108

Met Ala Ser Phe Arg Lys Leu Thr Leu Ser Glu Lys Val Pro Pro Glu

1 5 10 15

Ser Phe Ser Pro Thr Ala Met Asp Ala Ile Phe Gly Ser Leu

20 25 30

<210> 109

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 29

<400> 109

Phe Tyr Leu Ala Met Pro Phe Ala Thr Pro Met Glu Ala Glu Leu Lys

1 5 10 15

Pro Ser Ala Phe Glu Pro Ala Thr Glu Met Gln Lys Ser Val

20 25 30

<210> 110

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 30

<400> 110

Ala Met Asp Ala Ile Phe Gly Ser Leu Ser Asp Glu Gly Ser Gly His

1 5 10 15

Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr

20 25 30

<210> 111

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Breast cancer vaccine peptide 31

<400> 111

Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Glu Asn Ala Gly

1 5 10 15

Thr Gly Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu

20 25 30

<210> 112

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 1

<400> 112

Val Cys Ser Met Glu Gly Thr Trp Tyr Leu Val Gly Leu Val Ser Tyr

1 5 10 15

Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg

20 25 30

<210> 113

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 2

<400> 113

Val Arg Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Leu

1 5 10 15

Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly

20 25 30

<210> 114

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 3

<400> 114

Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Met

1 5 10 15

Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys

20 25 30

<210> 115

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 4

<400> 115

Leu Ala Ser Lys Met His Ser Leu Leu Ala Leu Met Val Gly Leu Pro

1 5 10 15

Lys Ser Met Thr Met Met Pro Ala Leu Phe Lys Glu Asn Arg

20 25 30

<210> 116

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 5

<400> 116

Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser Leu

1 5 10 15

Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala

20 25 30

<210> 117

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 6

<400> 117

Lys Phe Met Asn Pro Tyr Asn Ala Val Leu Thr Lys Lys Phe Gln Phe

1 5 10 15

Lys Lys Thr Met Ser Thr Phe His Asn Leu Val Ser Leu Asn

20 25 30

<210> 118

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 7

<400> 118

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala Lys

1 5 10 15

Val Asn Phe Phe Phe Glu Arg Ile Met Lys Tyr Glu Arg Leu

20 25 30

<210> 119

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 8

<400> 119

Lys Asp His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Pro

1 5 10 15

Glu Glu Ala Ile Trp Glu Ala Leu Ser Val Met Gly Leu Tyr

20 25 30

<210> 120

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 9

<400> 120

Tyr Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg Val

1 5 10 15

Cys Ser Met Glu Gly Thr Trp Tyr Leu Val Gly Leu Val Ser

20 25 30

<210> 121

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 10

<400> 121

Val Arg Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Thr

1 5 10 15

Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met

20 25 30

<210> 122

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 11

<400> 122

Leu Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly Lys

1 5 10 15

Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser

20 25 30

<210> 123

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 12

<400> 123

Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Pro

1 5 10 15

Glu Glu Ala Ile Trp Glu Ala Leu Ser Val Met Gly Leu Tyr

20 25 30

<210> 124

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 13

<400> 124

Leu Ala Ser Lys Met His Ser Leu Leu Ala Leu Met Val Gly Leu Lys

1 5 10 15

Asp His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu

20 25 30

<210> 125

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 14

<400> 125

Pro Lys Ser Met Thr Met Met Pro Ala Leu Phe Lys Glu Asn Arg Leu

1 5 10 15

Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala

20 25 30

<210> 126

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 15

<400> 126

Lys Phe Met Asn Pro Tyr Asn Ala Val Leu Thr Lys Lys Phe Gln Lys

1 5 10 15

Val Asn Phe Phe Phe Glu Arg Ile Met Lys Tyr Glu Arg Leu

20 25 30

<210> 127

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 16

<400> 127

Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala Phe

1 5 10 15

Lys Lys Thr Met Ser Thr Phe His Asn Leu Val Ser Leu Asn

20 25 30

<210> 128

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 17

<400> 128

Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg Asp Pro Glu Ala Val

1 5 10 15

Cys Ser Met Glu Gly Thr Trp Tyr Leu Val Gly Leu Val Ser

20 25 30

<210> 129

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 18

<400> 129

Pro Lys Ser Met Thr Met Met Pro Ala Leu Phe Lys Glu Asn Arg Gly

1 5 10 15

Asn Ile Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu

20 25 30

<210> 130

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 19

<400> 130

Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly Lys Ser

1 5 10 15

Arg Tyr Arg Ala Gln Arg Phe Trp Ser Trp Val Gly Gln Ala

20 25 30

<210> 131

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 20

<400> 131

Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser Met Gln Gly Leu Lys Asp

1 5 10 15

Glu Lys Val Ala Glu Leu Val Arg Phe Leu Leu Arg Lys Tyr

20 25 30

<210> 132

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 21

<400> 132

Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg Asp Gly

1 5 10 15

Thr Gly Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu

20 25 30

<210> 133

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 22

<400> 133

Ser Arg Ala Pro Glu Glu Ala Ile Trp Glu Ala Leu Ser Val Met Gln

1 5 10 15

Tyr Phe Val Gln Glu Asn Tyr Leu Glu Tyr Arg Gln Val Pro

20 25 30

<210> 134

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 23

<400> 134

Pro Lys Ser Met Thr Met Met Pro Ala Leu Phe Lys Glu Asn Arg Ser

1 5 10 15

Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

20 25 30

<210> 135

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 24

<400> 135

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser Arg

1 5 10 15

Asn Ser Ile Arg Ser Ser Phe Ile Ser Ser Leu Ser Phe Phe

20 25 30

<210> 136

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 25

<400> 136

Asn Ile Glu Asn Tyr Ser Thr Asn Ala Leu Ile Gln Pro Val Asp Glu

1 5 10 15

Lys Val Ala Glu Leu Val Arg Phe Leu Leu Arg Lys Tyr Gln

20 25 30

<210> 137

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 26

<400> 137

Arg Gln Phe Glu Thr Val Cys Lys Phe His Trp Val Glu Ala Phe Lys

1 5 10 15

Leu Leu Thr Gln Tyr Phe Val Gln Glu Asn Tyr Leu Glu Tyr

20 25 30

<210> 138

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 27

<400> 138

Glu Phe Leu Trp Gly Pro Arg Ala Leu Ala Glu Thr Ser Tyr Val Lys

1 5 10 15

Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu Glu Tyr

20 25 30

<210> 139

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 28

<400> 139

Ala Ser Ser Ser Ser Thr Leu Ile Met Gly Thr Leu Glu Glu Val Gln

1 5 10 15

Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser

20 25 30

<210> 140

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 29

<400> 140

Ser Arg Thr Leu Leu Leu Ala Leu Pro Leu Pro Leu Ser Leu Leu Ile

1 5 10 15

Gly His Leu Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr

20 25 30

<210> 141

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 30

<400> 141

Phe Ile Ile Val Val Phe Val Tyr Leu Thr Val Glu Asn Lys Ser Ile

1 5 10 15

Gly His Val Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr

20 25 30

<210> 142

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Colorectal cancer vaccine peptide 31

<400> 142

Leu Leu Ala Ala Ala Thr Ala Thr Phe Ala Ala Ala Gln Glu Glu Gln

1 5 10 15

Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser

20 25 30

<210> 143

<211> 1321

<212> PRT

<213> Artificial sequence

<220>

<223> SPAG9 antigen

<400> 143

Met Glu Leu Glu Asp Gly Val Val Tyr Gln Glu Glu Pro Gly Gly Ser

1 5 10 15

Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser Ile Tyr

20 25 30

Arg Glu Phe Glu Arg Leu Ile Gly Arg Tyr Asp Glu Glu Val Val Lys

35 40 45

Glu Leu Met Pro Leu Val Val Ala Val Leu Glu Asn Leu Asp Ser Val

50 55 60

Phe Ala Gln Asp Gln Glu His Gln Val Glu Leu Glu Leu Leu Arg Asp

65 70 75 80

Asp Asn Glu Gln Leu Ile Thr Gln Tyr Glu Arg Glu Lys Ala Leu Arg

85 90 95

Lys His Ala Glu Glu Lys Phe Ile Glu Phe Glu Asp Ser Gln Glu Gln

100 105 110

Glu Lys Lys Asp Leu Gln Thr Arg Val Glu Ser Leu Glu Ser Gln Thr

115 120 125

Arg Gln Leu Glu Leu Lys Ala Lys Asn Tyr Ala Asp Gln Ile Ser Arg

130 135 140

Leu Glu Glu Arg Glu Ala Glu Leu Lys Lys Glu Tyr Asn Ala Leu His

145 150 155 160

Gln Arg His Thr Glu Met Ile His Asn Tyr Met Glu His Leu Glu Arg

165 170 175

Thr Lys Leu His Gln Leu Ser Gly Ser Asp Gln Leu Glu Ser Thr Ala

180 185 190

His Ser Arg Ile Arg Lys Glu Arg Pro Ile Ser Leu Gly Ile Phe Pro

195 200 205

Leu Pro Ala Gly Asp Gly Leu Leu Thr Pro Asp Ala Gln Lys Gly Gly

210 215 220

Glu Thr Pro Gly Ser Glu Gln Trp Lys Phe Gln Glu Leu Ser Gln Pro

225 230 235 240

Arg Ser His Thr Ser Leu Lys Val Ser Asn Ser Pro Glu Pro Gln Lys

245 250 255

Ala Val Glu Gln Glu Asp Glu Leu Ser Asp Val Ser Gln Gly Gly Ser

260 265 270

Lys Ala Thr Thr Pro Ala Ser Thr Ala Asn Ser Asp Val Ala Thr Ile

275 280 285

Pro Thr Asp Thr Pro Leu Lys Glu Glu Asn Glu Gly Phe Val Lys Val

290 295 300

Thr Asp Ala Pro Asn Lys Ser Glu Ile Ser Lys His Ile Glu Val Gln

305 310 315 320

Val Ala Gln Glu Thr Arg Asn Val Ser Thr Gly Ser Ala Glu Asn Glu

325 330 335

Glu Lys Ser Glu Val Gln Ala Ile Ile Glu Ser Thr Pro Glu Leu Asp

340 345 350

Met Asp Lys Asp Leu Ser Gly Tyr Lys Gly Ser Ser Thr Pro Thr Lys

355 360 365

Gly Ile Glu Asn Lys Ala Phe Asp Arg Asn Thr Glu Ser Leu Phe Glu

370 375 380

Glu Leu Ser Ser Ala Gly Ser Gly Leu Ile Gly Asp Val Asp Glu Gly

385 390 395 400

Ala Asp Leu Leu Gly Met Gly Arg Glu Val Glu Asn Leu Ile Leu Glu

405 410 415

Asn Thr Gln Leu Leu Glu Thr Lys Asn Ala Leu Asn Ile Val Lys Asn

420 425 430

Asp Leu Ile Ala Lys Val Asp Glu Leu Thr Cys Glu Lys Asp Val Leu

435 440 445

Gln Gly Glu Leu Glu Ala Val Lys Gln Ala Lys Leu Lys Leu Glu Glu

450 455 460

Lys Asn Arg Glu Leu Glu Glu Glu Leu Arg Lys Ala Arg Ala Glu Ala

465 470 475 480

Glu Asp Ala Arg Gln Lys Ala Lys Asp Asp Asp Asp Ser Asp Ile Pro

485 490 495

Thr Ala Gln Arg Lys Arg Phe Thr Arg Val Glu Met Ala Arg Val Leu

500 505 510

Met Glu Arg Asn Gln Tyr Lys Glu Arg Leu Met Glu Leu Gln Glu Ala

515 520 525

Val Arg Trp Thr Glu Met Ile Arg Ala Ser Arg Glu Asn Pro Ala Met

530 535 540

Gln Glu Lys Lys Arg Ser Ser Ile Trp Gln Phe Phe Ser Arg Leu Phe

545 550 555 560

Ser Ser Ser Ser Asn Thr Thr Lys Lys Pro Glu Pro Pro Val Asn Leu

565 570 575

Lys Tyr Asn Ala Pro Thr Ser His Val Thr Pro Ser Val Lys Lys Arg

580 585 590

Ser Ser Thr Leu Ser Gln Leu Pro Gly Asp Lys Ser Lys Ala Phe Asp

595 600 605

Phe Leu Ser Glu Glu Thr Glu Ala Ser Leu Ala Ser Arg Arg Glu Gln

610 615 620

Lys Arg Glu Gln Tyr Arg Gln Val Lys Ala His Val Gln Lys Glu Asp

625 630 635 640

Gly Arg Val Gln Ala Phe Gly Trp Ser Leu Pro Gln Lys Tyr Lys Gln

645 650 655

Val Thr Asn Gly Gln Gly Glu Asn Lys Met Lys Asn Leu Pro Val Pro

660 665 670

Val Tyr Leu Arg Pro Leu Asp Glu Lys Asp Thr Ser Met Lys Leu Trp

675 680 685

Cys Ala Val Gly Val Asn Leu Ser Gly Gly Lys Thr Arg Asp Gly Gly

690 695 700

Ser Val Val Gly Ala Ser Val Phe Tyr Lys Asp Val Ala Gly Leu Asp

705 710 715 720

Thr Glu Gly Ser Lys Gln Arg Ser Ala Ser Gln Ser Ser Leu Asp Lys

725 730 735

Leu Asp Gln Glu Leu Lys Glu Gln Gln Lys Glu Leu Lys Asn Gln Glu

740 745 750

Glu Leu Ser Ser Leu Val Trp Ile Cys Thr Ser Thr His Ser Ala Thr

755 760 765

Lys Val Leu Ile Ile Asp Ala Val Gln Pro Gly Asn Ile Leu Asp Ser

770 775 780

Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala Ser Val Pro Gly

785 790 795 800

Ala Arg Glu Thr Asp Tyr Pro Ala Gly Glu Asp Leu Ser Glu Ser Gly

805 810 815

Gln Val Asp Lys Ala Ser Leu Cys Gly Ser Met Thr Ser Asn Ser Ser

820 825 830

Ala Glu Thr Asp Ser Leu Leu Gly Gly Ile Thr Val Val Gly Cys Ser

835 840 845

Ala Glu Gly Val Thr Gly Ala Ala Thr Ser Pro Ser Thr Asn Gly Ala

850 855 860

Ser Pro Val Met Asp Lys Pro Pro Glu Met Glu Ala Glu Asn Ser Glu

865 870 875 880

Val Asp Glu Asn Val Pro Thr Ala Glu Glu Ala Thr Glu Ala Thr Glu

885 890 895

Gly Asn Ala Gly Ser Ala Glu Asp Thr Val Asp Ile Ser Gln Thr Gly

900 905 910

Val Tyr Thr Glu His Val Phe Thr Asp Pro Leu Gly Val Gln Ile Pro

915 920 925

Glu Asp Leu Ser Pro Val Tyr Gln Ser Ser Asn Asp Ser Asp Ala Tyr

930 935 940

Lys Asp Gln Ile Ser Val Leu Pro Asn Glu Gln Asp Leu Val Arg Glu

945 950 955 960

Glu Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Trp Leu Gly Ala

965 970 975

Gln Asn Gly Cys Leu Tyr Val His Ser Ser Val Ala Gln Trp Arg Lys

980 985 990

Cys Leu His Ser Ile Lys Leu Lys Asp Ser Ile Leu Ser Ile Val His

995 1000 1005

Val Lys Gly Ile Val Leu Val Ala Leu Ala Asp Gly Thr Leu Ala

1010 1015 1020

Ile Phe His Arg Gly Val Asp Gly Gln Trp Asp Leu Ser Asn Tyr

1025 1030 1035

His Leu Leu Asp Leu Gly Arg Pro His His Ser Ile Arg Cys Met

1040 1045 1050

Thr Val Val His Asp Lys Val Trp Cys Gly Tyr Arg Asn Lys Ile

1055 1060 1065

Tyr Val Val Gln Pro Lys Ala Met Lys Ile Glu Lys Ser Phe Asp

1070 1075 1080

Ala His Pro Arg Lys Glu Ser Gln Val Arg Gln Leu Ala Trp Val

1085 1090 1095

Gly Asp Gly Val Trp Val Ser Ile Arg Leu Asp Ser Thr Leu Arg

1100 1105 1110

Leu Tyr His Ala His Thr Tyr Gln His Leu Gln Asp Val Asp Ile

1115 1120 1125

Glu Pro Tyr Val Ser Lys Met Leu Gly Thr Gly Lys Leu Gly Phe

1130 1135 1140

Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser Cys Asn Arg Leu

1145 1150 1155

Trp Val Gly Thr Gly Asn Gly Val Ile Ile Ser Ile Pro Leu Thr

1160 1165 1170

Glu Thr Asn Lys Thr Ser Gly Val Pro Gly Asn Arg Pro Gly Ser

1175 1180 1185

Val Ile Arg Val Tyr Gly Asp Glu Asn Ser Asp Lys Val Thr Pro

1190 1195 1200

Gly Thr Phe Ile Pro Tyr Cys Ser Met Ala His Ala Gln Leu Cys

1205 1210 1215

Phe His Gly His Arg Asp Ala Val Lys Phe Phe Val Ala Val Pro

1220 1225 1230

Gly Gln Val Ile Ser Pro Gln Ser Ser Ser Ser Gly Thr Asp Leu

1235 1240 1245

Thr Gly Asp Lys Ala Gly Pro Ser Ala Gln Glu Pro Gly Ser Gln

1250 1255 1260

Thr Pro Leu Lys Ser Met Leu Val Ile Ser Gly Gly Glu Gly Tyr

1265 1270 1275

Ile Asp Phe Arg Met Gly Asp Glu Gly Gly Glu Ser Glu Leu Leu

1280 1285 1290

Gly Glu Asp Leu Pro Leu Glu Pro Ser Val Thr Lys Ala Glu Arg

1295 1300 1305

Ser His Leu Ile Val Trp Gln Val Met Tyr Gly Asn Glu

1310 1315 1320

<210> 144

<211> 854

<212> PRT

<213> Artificial sequence

<220>

<223> AKAP-4 antigen

<400> 144

Met Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp Trp

1 5 10 15

Leu Arg Ser His Arg Gly Val Cys Lys Val Asp Leu Tyr Asn Pro Glu

20 25 30

Gly Gln Gln Asp Gln Asp Arg Lys Val Ile Cys Phe Val Asp Val Ser

35 40 45

Thr Leu Asn Val Glu Asp Lys Asp Tyr Lys Asp Ala Ala Ser Ser Ser

50 55 60

Ser Glu Gly Asn Leu Asn Leu Gly Ser Leu Glu Glu Lys Glu Ile Ile

65 70 75 80

Val Ile Lys Asp Thr Glu Lys Lys Asp Gln Ser Lys Thr Glu Gly Ser

85 90 95

Val Cys Leu Phe Lys Gln Ala Pro Ser Asp Pro Val Ser Val Leu Asn

100 105 110

Trp Leu Leu Ser Asp Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala

115 120 125

Leu Ser Pro Ser Thr Ser Ser Thr Cys Lys His Lys Val Gly Asp Thr Glu

130 135 140

Gly Glu Tyr His Arg Ala Ser Ser Glu Asn Cys Tyr Ser Val Tyr Ala

145 150 155 160

Asp Gln Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg

165 170 175

Leu Glu Met Thr Ala Ala Lys Asn Thr Asn Asn Asn Gln Ser Pro Ser

180 185 190

Ala Pro Pro Ala Lys Pro Pro Ser Thr Gln Arg Ala Val Ile Ser Pro

195 200 205

Asp Gly Glu Cys Ser Ile Asp Asp Leu Ser Phe Tyr Val Asn Arg Leu

210 215 220

Ser Ser Leu Val Ile Gln Met Ala His Lys Glu Ile Lys Glu Lys Leu

225 230 235 240

Glu Gly Lys Ser Lys Cys Leu His His Ser Ile Cys Pro Ser Pro Gly

245 250 255

Asn Lys Glu Arg Ile Ser Pro Arg Thr Pro Ala Ser Lys Ile Ala Ser

260 265 270

Glu Met Ala Tyr Glu Ala Val Glu Leu Thr Ala Ala Glu Met Arg Gly

275 280 285

Thr Gly Glu Glu Ser Arg Glu Gly Gly Gln Lys Ser Phe Leu Tyr Ser

290 295 300

Glu Leu Ser Asn Lys Ser Lys Ser Gly Asp Lys Gln Met Ser Gln Arg

305 310 315 320

Glu Ser Lys Glu Phe Ala Asp Ser Ile Ser Lys Gly Leu Met Val Tyr

325 330 335

Ala Asn Gln Val Ala Ser Asp Met Met Val Ser Leu Met Lys Thr Leu

340 345 350

Lys Val His Ser Ser Gly Lys Pro Ile Pro Ala Ser Val Val Leu Lys

355 360 365

Arg Val Leu Leu Arg His Thr Lys Glu Ile Val Ser Asp Leu Ile Asp

370 375 380

Ser Cys Met Lys Asn Leu His Asn Ile Thr Gly Val Leu Met Thr Asp

385 390 395 400

Ser Asp Phe Val Ser Ala Val Lys Arg Asn Leu Phe Asn Gln Trp Lys

405 410 415

Gln Asn Ala Thr Asp Ile Met Glu Ala Met Leu Lys Arg Leu Val Ser

420 425 430

Ala Leu Ile Gly Glu Glu Lys Glu Thr Lys Ser Gln Ser Leu Ser Tyr

435 440 445

Ala Ser Leu Lys Ala Gly Ser His Asp Pro Lys Cys Arg Asn Gln Ser

450 455 460

Leu Glu Phe Ser Thr Met Lys Ala Glu Met Lys Glu Arg Asp Lys Gly

465 470 475 480

Lys Met Lys Ser Asp Pro Cys Lys Ser Leu Thr Ser Ala Glu Lys Val

485 490 495

Gly Glu His Ile Leu Lys Glu Gly Leu Thr Ile Trp Asn Gln Lys Gln

500 505 510

Gly Asn Ser Cys Lys Val Ala Thr Lys Ala Cys Ser Asn Lys Asp Glu

515 520 525

Lys Gly Glu Lys Ile Asn Ala Ser Thr Asp Ser Leu Ala Lys Asp Leu

530 535 540

Ile Val Ser Ala Leu Lys Leu Ile Gln Tyr His Leu Thr Gln Gln Thr

545 550 555 560

Lys Gly Lys Asp Thr Cys Glu Glu Asp Cys Pro Gly Ser Thr Met Gly

565 570 575

Tyr Met Ala Gln Ser Thr Gln Tyr Glu Lys Cys Gly Gly Gly Gln Ser

580 585 590

Ala Lys Ala Leu Ser Val Lys Gln Leu Glu Ser His Arg Ala Pro Gly

595 600 605

Pro Ser Thr Cys Gln Lys Glu Asn Gln His Leu Asp Ser Gln Lys Met

610 615 620

Asp Met Ser Asn Ile Val Leu Met Leu Ile Gln Lys Leu Leu Asn Glu

625 630 635 640

Asn Pro Phe Lys Cys Glu Asp Pro Cys Glu Gly Glu Asn Lys Cys Ser

645 650 655

Glu Pro Arg Ala Ser Lys Ala Ala Ser Met Ser Asn Arg Ser Asp Lys

660 665 670

Ala Glu Glu Gln Cys Gln Glu His Gln Glu Leu Asp Cys Thr Ser Gly

675 680 685

Met Lys Gln Ala Asn Gly Gln Phe Ile Asp Lys Leu Val Glu Ser Val

690 695 700

Met Lys Leu Cys Leu Ile Met Ala Lys Tyr Ser Asn Asp Gly Ala Ala

705 710 715 720

Leu Ala Glu Leu Glu Glu Gln Ala Ala Ser Ala Asn Lys Pro Asn Phe

725 730 735

Arg Gly Thr Arg Cys Ile His Ser Gly Ala Met Pro Gln Asn Tyr Gln

740 745 750

Asp Ser Leu Gly His Glu Val Ile Val Asn Asn Gln Cys Ser Thr Asn

755 760 765

Ser Leu Gln Lys Gln Leu Gln Ala Val Leu Gln Trp Ile Ala Ala Ser

770 775 780

Gln Phe Asn Val Pro Met Leu Tyr Phe Met Gly Asp Lys Asp Gly Gln

785 790 795 800

Leu Glu Lys Leu Pro Gln Val Ser Ala Lys Ala Ala Glu Lys Gly Tyr

805 810 815

Ser Val Gly Gly Leu Leu Gln Glu Val Met Lys Phe Ala Lys Glu Arg

820 825 830

Gln Pro Asp Glu Ala Val Gly Lys Val Ala Arg Lys Gln Leu Leu Asp

835 840 845

Trp Leu Leu Ala Asn Leu

850

<210> 145

<211> 663

<212> PRT

<213> Artificial sequence

<220>

<223> BORIS antigen

<400> 145

Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ile

1 5 10 15

Lys Glu Leu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys

20 25 30

Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser Glu Leu Glu

35 40 45

Ala Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu

50 55 60

Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu

65 70 75 80

Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala Val Glu Leu Gln Asp

85 90 95

Met Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val

100 105 110

Gln Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln

115 120 125

Ser Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu Leu Tyr Ser

130 135 140

Pro Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val

145 150 155 160

Met Val Ala Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr

165 170 175

Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln Leu Leu

180 185 190

Ala Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly

195 200 205

Asp Glu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val

210 215 220

Glu Glu Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys

225 230 235 240

Ala Lys Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr

245 250 255

Phe His Cys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe

260 265 270

Asn Arg His Met Lys Thr His Thr Ser Glu Lys Pro His Leu Cys His

275 280 285

Leu Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val

290 295 300

Asn Thr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met

305 310 315 320

Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg Tyr Lys His

325 330 335

Thr His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val

340 345 350

Glu Ala Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg

355 360 365

Pro Phe Gln Cys Cys Gln Cys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys

370 375 380

Leu Lys Arg His Met Arg Thr His Ser Gly Glu Lys Pro Tyr Glu Cys

385 390 395 400

His Ile Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His

405 410 415

Ile Leu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln Cys Pro His

420 425 430

Cys Ala Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val His Met Arg

435 440 445

Asn Leu His Ala Tyr Ser Ala Ala Glu Leu Lys Cys Arg Tyr Cys Ser

450 455 460

Ala Val Phe His Glu Arg Tyr Ala Leu Ile Gln His Gln Lys Thr His

465 470 475 480

Lys Asn Glu Lys Arg Phe Lys Cys Lys His Cys Ser Tyr Ala Cys Lys

485 490 495

Gln Glu Arg His Met Thr Ala His Ile Arg Thr His Thr Gly Glu Lys

500 505 510

Pro Phe Thr Cys Leu Ser Cys Asn Lys Cys Phe Arg Gln Lys Gln Leu

515 520 525

Leu Asn Ala His Phe Arg Lys Tyr His Asp Ala Asn Phe Ile Pro Thr

530 535 540

Val Tyr Lys Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile Asn

545 550 555 560

Leu His Arg His Ser Glu Lys Cys Gly Ser Gly Glu Ala Lys Ser Ala

565 570 575

Ala Ser Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln Thr Ile Leu

580 585 590

Lys Glu Ala Thr Lys Gly Gln Lys Glu Ala Ala Lys Gly Trp Lys Glu

595 600 605

Ala Ala Asn Gly Asp Glu Ala Ala Ala Glu Glu Ala Ser Thr Thr Lys

610 615 620

Gly Glu Gln Phe Pro Gly Glu Met Phe Pro Val Ala Cys Arg Glu Thr

625 630 635 640

Thr Ala Arg Val Lys Glu Glu Val Asp Glu Gly Val Thr Cys Glu Met

645 650 655

Leu Leu Asn Thr Met Asp Lys

660

<210> 146

<211> 255

<212> PRT

<213> Artificial sequence

<220>

<223> NY-SAR-35

<400> 146

Met Ser Ser His Arg Arg Lys Ala Lys Gly Arg Asn Arg Arg Ser His

1 5 10 15

Arg Ala Met Arg Val Ala His Leu Glu Leu Ala Thr Tyr Glu Leu Ala

20 25 30

Ala Thr Glu Ser Asn Pro Glu Ser Ser His Pro Gly Tyr Glu Ala Ala

35 40 45

Met Ala Asp Arg Pro Gln Pro Gly Trp Arg Glu Ser Leu Lys Met Arg

50 55 60

Val Ser Lys Pro Phe Gly Met Leu Met Leu Ser Ile Trp Ile Leu Leu

65 70 75 80

Phe Val Cys Tyr Tyr Leu Ser Tyr Tyr Leu Cys Ser Gly Ser Ser Tyr

85 90 95

Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Glu Asn Ala His

100 105 110

Gly Gln Ser Leu Glu Glu Asp Ser Ala Leu Glu Ala Leu Leu Asn Phe

115 120 125

Phe Phe Pro Thr Thr Cys Asn Leu Arg Glu Asn Gln Val Ala Lys Pro

130 135 140

Cys Asn Glu Leu Gln Asp Leu Ser Glu Ser Glu Cys Leu Arg His Lys

145 150 155 160

Cys Cys Phe Ser Ser Ser Ser Gly Thr Thr Ser Phe Lys Cys Phe Ala Pro

165 170 175

Phe Arg Asp Val Pro Lys Gln Met Met Gln Met Phe Gly Leu Gly Ala

180 185 190

Ile Ser Leu Ile Leu Val Cys Leu Pro Ile Tyr Cys Arg Ser Leu Phe

195 200 205

Trp Arg Ser Glu Pro Ala Asp Asp Leu Gln Arg Gln Asp Asn Arg Val

210 215 220

Val Thr Gly Leu Lys Lys Gln Arg Arg Lys Arg Lys Arg Lys Ser Glu

225 230 235 240

Met Leu Gln Lys Ala Ala Arg Gly Arg Glu Glu His Gly Asp Glu

245 250 255

<210> 147

<211> 1341

<212> PRT

<213> Artificial sequence

<220>

<223> NY-BR-1

<400> 147

Met Thr Lys Arg Lys Lys Thr Ile Asn Leu Asn Ile Gln Asp Ala Gln

1 5 10 15

Lys Arg Thr Ala Leu His Trp Ala Cys Val Asn Gly His Glu Glu Val

20 25 30

Val Thr Phe Leu Val Asp Arg Lys Cys Gln Leu Asp Val Leu Asp Gly

35 40 45

Glu His Arg Thr Pro Leu Met Lys Ala Leu Gln Cys His Gln Glu Ala

50 55 60

Cys Ala Asn Ile Leu Ile Asp Ser Gly Ala Asp Ile Asn Leu Val Asp

65 70 75 80

Val Tyr Gly Asn Thr Ala Leu His Tyr Ala Val Tyr Ser Glu Ile Leu

85 90 95

Ser Val Val Ala Lys Leu Leu Ser His Gly Ala Val Ile Glu Val His

100 105 110

Asn Lys Ala Ser Leu Thr Pro Leu Leu Leu Ser Ile Thr Lys Arg Ser

115 120 125

Glu Gln Ile Val Glu Phe Leu Leu Ile Lys Asn Ala Asn Ala Asn Ala

130 135 140

Val Asn Lys Tyr Lys Cys Thr Ala Leu Met Leu Ala Val Cys His Gly

145 150 155 160

Ser Ser Glu Ile Val Gly Met Leu Leu Gln Gln Asn Val Asp Val Phe

165 170 175

Ala Ala Asp Ile Cys Gly Val Thr Ala Glu His Tyr Ala Val Thr Cys

180 185 190

Gly Phe His His Ile His Glu Gln Ile Met Glu Tyr Ile Arg Lys Leu

195 200 205

Ser Lys Asn His Gln Asn Thr Asn Pro Glu Gly Thr Ser Ala Gly Thr

210 215 220

Pro Asp Glu Ala Ala Pro Leu Ala Glu Arg Thr Pro Asp Thr Ala Glu

225 230 235 240

Ser Leu Val Glu Lys Thr Pro Asp Glu Ala Ala Pro Leu Val Glu Arg

245 250 255

Thr Pro Asp Thr Ala Glu Ser Leu Val Glu Lys Thr Pro Asp Glu Ala

260 265 270

Ala Ser Leu Val Glu Gly Thr Ser Asp Lys Ile Gln Cys Leu Glu Lys

275 280 285

Ala Thr Ser Gly Lys Phe Glu Gln Ser Ala Glu Glu Thr Pro Arg Glu

290 295 300

Ile Thr Ser Pro Ala Lys Glu Thr Ser Glu Lys Phe Thr Trp Pro Ala

305 310 315 320

Lys Gly Arg Pro Arg Lys Ile Ala Trp Glu Lys Lys Glu Asp Thr Pro

325 330 335

Arg Glu Ile Met Ser Pro Ala Lys Glu Thr Ser Glu Lys Phe Thr Trp

340 345 350

Ala Ala Lys Gly Arg Pro Arg Lys Ile Ala Trp Glu Lys Lys Glu Thr

355 360 365

Pro Val Lys Thr Gly Cys Val Ala Arg Val Thr Ser Asn Lys Thr Lys

370 375 380

Val Leu Glu Lys Gly Arg Ser Lys Met Ile Ala Cys Pro Thr Lys Glu

385 390 395 400

Ser Ser Thr Lys Ala Ser Ala Asn Asp Gln Arg Phe Pro Ser Glu Ser

405 410 415

Lys Gln Glu Glu Asp Glu Glu Tyr Ser Cys Asp Ser Arg Ser Leu Phe

420 425 430

Glu Ser Ser Ala Lys Ile Gln Val Cys Ile Pro Glu Ser Ile Tyr Gln

435 440 445

Lys Val Met Glu Ile Asn Arg Glu Val Glu Glu Pro Pro Lys Lys Pro

450 455 460

Ser Ala Phe Lys Pro Ala Ile Glu Met Gln Asn Ser Val Pro Asn Lys

465 470 475 480

Ala Phe Glu Leu Lys Asn Glu Gln Thr Leu Arg Ala Asp Pro Met Phe

485 490 495

Pro Pro Glu Ser Lys Gln Lys Asp Tyr Glu Glu Asn Ser Trp Asp Ser

500 505 510

Glu Ser Leu Cys Glu Thr Val Ser Gln Lys Asp Val Cys Leu Pro Lys

515 520 525

Ala Thr His Gln Lys Glu Ile Asp Lys Ile Asn Gly Lys Leu Glu Glu

530 535 540

Ser Pro Asn Lys Asp Gly Leu Leu Lys Ala Thr Cys Gly Met Lys Val

545 550 555 560

Ser Ile Pro Thr Lys Ala Leu Glu Leu Lys Asp Met Gln Thr Phe Lys

565 570 575

Ala Glu Pro Pro Gly Lys Pro Ser Ala Phe Glu Pro Ala Thr Glu Met

580 585 590

Gln Lys Ser Val Pro Asn Lys Ala Leu Glu Leu Lys Asn Glu Gln Thr

595 600 605

Leu Arg Ala Asp Glu Ile Leu Pro Ser Glu Ser Lys Gln Lys Asp Tyr

610 615 620

Glu Glu Asn Ser Trp Asp Thr Glu Ser Leu Cys Glu Thr Val Ser Gln

625 630 635 640

Lys Asp Val Cys Leu Pro Lys Ala Ala His Gln Lys Glu Ile Asp Lys

645 650 655

Ile Asn Gly Lys Leu Glu Gly Ser Pro Val Lys Asp Gly Leu Leu Lys

660 665 670

Ala Asn Cys Gly Met Lys Val Ser Ile Pro Thr Lys Ala Leu Glu Leu

675 680 685

Met Asp Met Gln Thr Phe Lys Ala Glu Pro Pro Glu Lys Pro Ser Ala

690 695 700

Phe Glu Pro Ala Ile Glu Met Gln Lys Ser Val Pro Asn Lys Ala Leu

705 710 715 720

Glu Leu Lys Asn Glu Gln Thr Leu Arg Ala Asp Glu Ile Leu Pro Ser

725 730 735

Glu Ser Lys Gln Lys Asp Tyr Glu Glu Ser Ser Trp Asp Ser Glu Ser

740 745 750

Leu Cys Glu Thr Val Ser Gln Lys Asp Val Cys Leu Pro Lys Ala Thr

755 760 765

His Gln Lys Glu Ile Asp Lys Ile Asn Gly Lys Leu Glu Glu Ser Pro

770 775 780

Asp Asn Asp Gly Phe Leu Lys Ala Pro Cys Arg Met Lys Val Ser Ile

785 790 795 800

Pro Thr Lys Ala Leu Glu Leu Met Asp Met Gln Thr Phe Lys Ala Glu

805 810 815

Pro Pro Glu Lys Pro Ser Ala Phe Glu Pro Ala Ile Glu Met Gln Lys

820 825 830

Ser Val Pro Asn Lys Ala Leu Glu Leu Lys Asn Glu Gln Thr Leu Arg

835 840 845

Ala Asp Gln Met Phe Pro Ser Glu Ser Lys Gln Lys Lys Val Glu Glu

850 855 860

Asn Ser Trp Asp Ser Glu Ser Leu Arg Glu Thr Val Ser Gln Lys Asp

865 870 875 880

Val Cys Val Pro Lys Ala Thr His Gln Lys Glu Met Asp Lys Ile Ser

885 890 895

Gly Lys Leu Glu Asp Ser Thr Ser Leu Ser Lys Ile Leu Asp Thr Val

900 905 910

His Ser Cys Glu Arg Ala Arg Glu Leu Gln Lys Asp His Cys Glu Gln

915 920 925

Arg Thr Gly Lys Met Glu Gln Met Lys Lys Lys Phe Cys Val Leu Lys

930 935 940

Lys Lys Leu Ser Glu Ala Lys Glu Ile Lys Ser Gln Leu Glu Asn Gln

945 950 955 960

Lys Val Lys Trp Glu Gln Glu Leu Cys Ser Val Arg Leu Thr Leu Asn

965 970 975

Gln Glu Glu Glu Lys Arg Arg Asn Ala Asp Ile Leu Asn Glu Lys Ile

980 985 990

Arg Glu Glu Leu Gly Arg Ile Glu Glu Gln His Arg Lys Glu Leu Glu

995 1000 1005

Val Lys Gln Gln Leu Glu Gln Ala Leu Arg Ile Gln Asp Ile Glu

1010 1015 1020

Leu Lys Ser Val Glu Ser Asn Leu Asn Gln Val Ser His Thr His

1025 1030 1035

Glu Asn Glu Asn Tyr Leu Leu His Glu Asn Cys Met Leu Lys Lys

1040 1045 1050

Glu Ile Ala Met Leu Lys Leu Glu Ile Ala Thr Leu Lys His Gln

1055 1060 1065

Tyr Gln Glu Lys Glu Asn Lys Tyr Phe Glu Asp Ile Lys Ile Leu

1070 1075 1080

Lys Glu Lys Asn Ala Glu Leu Gln Met Thr Leu Lys Leu Lys Glu

1085 1090 1095

Glu Ser Leu Thr Lys Arg Ala Ser Gln Tyr Ser Gly Gln Leu Lys

1100 1105 1110

Val Leu Ile Ala Glu Asn Thr Met Leu Thr Ser Lys Leu Lys Glu

1115 1120 1125

Lys Gln Asp Lys Glu Ile Leu Glu Ala Glu Ile Glu Ser His His

1130 1135 1140

Pro Arg Leu Ala Ser Ala Val Gln Asp His Asp Gln Ile Val Thr

1145 1150 1155

Ser Arg Lys Ser Gln Glu Pro Ala Phe His Ile Ala Gly Asp Ala

1160 1165 1170

Cys Leu Gln Arg Lys Met Asn Val Asp Val Ser Ser Thr Ile Tyr

1175 1180 1185

Asn Asn Glu Val Leu His Gln Pro Leu Ser Glu Ala Gln Arg Lys

1190 1195 1200

Ser Lys Ser Leu Lys Ile Asn Leu Asn Tyr Ala Gly Asp Ala Leu

1205 1210 1215

Arg Glu Asn Thr Leu Val Ser Glu His Ala Gln Arg Asp Gln Arg

1220 1225 1230

Glu Thr Gln Cys Gln Met Lys Glu Ala Glu His Met Tyr Gln Asn

1235 1240 1245

Glu Gln Asp Asn Val Asn Lys His Thr Glu Gln Gln Glu Ser Leu

1250 1255 1260

Asp Gln Lys Leu Phe Gln Leu Gln Ser Lys Asn Met Trp Leu Gln

1265 1270 1275

Gln Gln Leu Val His Ala His Lys Lys Ala Asp Asn Lys Ser Lys

1280 1285 1290

Ile Thr Ile Asp Ile His Phe Leu Glu Arg Lys Met Gln His His

1295 1300 1305

Leu Leu Lys Glu Lys Asn Glu Glu Ile Phe Asn Tyr Asn Asn His

1310 1315 1320

Leu Lys Asn Arg Ile Tyr Gln Tyr Glu Lys Glu Lys Ala Glu Thr

1325 1330 1335

Glu Asn Ser

1340

<210> 148

<211> 142

<212> PRT

<213> Artificial sequence

<220>

<223> SURVIVIN Antigen

<400> 148

Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp

1 5 10 15

His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala

20 25 30

Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr

35 40 45

Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu

50 55 60

Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His

65 70 75 80

Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu

85 90 95

Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys

100 105 110

Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala

115 120 125

Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp

130 135 140

<210> 149

<211> 429

<212> PRT

<213> Artificial sequence

<220>

<223> MAGE-A11

<400> 149

Met Glu Thr Gln Phe Arg Arg Gly Gly Leu Gly Cys Ser Pro Ala Ser

1 5 10 15

Ile Lys Arg Lys Lys Lys Arg Glu Asp Ser Gly Asp Phe Gly Leu Gln

20 25 30

Val Ser Thr Met Phe Ser Glu Asp Asp Phe Gln Ser Thr Glu Arg Ala

35 40 45

Pro Tyr Gly Pro Gln Leu Gln Trp Ser Gln Asp Leu Pro Arg Val Gln

50 55 60

Val Phe Arg Glu Gln Ala Asn Leu Glu Asp Arg Ser Pro Arg Arg Thr

65 70 75 80

Gln Arg Ile Thr Gly Gly Glu Gln Val Leu Trp Gly Pro Ile Thr Gln

85 90 95

Ile Phe Pro Thr Val Arg Pro Ala Asp Leu Thr Arg Val Ile Met Pro

100 105 110

Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu Gln Ala

115 120 125

Gln Glu Glu Asp Leu Gly Leu Val Gly Ala Gln Ala Leu Gln Ala Glu

130 135 140

Glu Gln Glu Ala Ala Phe Phe Ser Ser Thr Leu Asn Val Gly Thr Leu

145 150 155 160

Glu Glu Leu Pro Ala Ala Glu Ser Pro Ser Pro Pro Gln Ser Pro Gln

165 170 175

Glu Glu Ser Phe Ser Pro Thr Ala Met Asp Ala Ile Phe Gly Ser Leu

180 185 190

Ser Asp Glu Gly Ser Gly Ser Gln Glu Lys Glu Gly Pro Ser Thr Ser

195 200 205

Pro Asp Leu Ile Asp Pro Glu Ser Phe Ser Gln Asp Ile Leu His Asp

210 215 220

Lys Ile Ile Asp Leu Val His Leu Leu Leu Arg Lys Tyr Arg Val Lys

225 230 235 240

Gly Leu Ile Thr Lys Ala Glu Met Leu Gly Ser Val Ile Lys Asn Tyr

245 250 255

Glu Asp Tyr Phe Pro Glu Ile Phe Arg Glu Ala Ser Val Cys Met Gln

260 265 270

Leu Leu Phe Gly Ile Asp Val Lys Glu Val Asp Pro Thr Ser His Ser

275 280 285

Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr Asp Gly Ile Gln Cys

290 295 300

Asn Glu Gln Ser Met Pro Lys Ser Gly Leu Leu Ile Ile Val Leu Gly

305 310 315 320

Val Ile Phe Met Glu Gly Asn Cys Ile Pro Glu Glu Val Met Trp Glu

325 330 335

Val Leu Ser Ile Met Gly Val Tyr Ala Gly Arg Glu His Phe Leu Phe

340 345 350

Gly Glu Pro Lys Arg Leu Leu Thr Gln Asn Trp Val Gln Glu Lys Tyr

355 360 365

Leu Val Tyr Arg Gln Val Pro Gly Thr Asp Pro Ala Cys Tyr Glu Phe

370 375 380

Leu Trp Gly Pro Arg Ala His Ala Glu Thr Ser Lys Met Lys Val Leu

385 390 395 400

Glu Tyr Ile Ala Asn Ala Asn Gly Arg Asp Pro Thr Ser Tyr Pro Ser

405 410 415

Leu Tyr Glu Asp Ala Leu Arg Glu Glu Gly Glu Gly Val

420 425

<210> 150

<211> 509

<212> PRT

<213> Artificial sequence

<220>

<223> PRAME antigen

<400> 150

Met Glu Arg Arg Arg Leu Trp Gly Ser Ile Gln Ser Arg Tyr Ile Ser

1 5 10 15

Met Ser Val Trp Thr Ser Pro Arg Arg Leu Val Glu Leu Ala Gly Gln

20 25 30

Ser Leu Leu Lys Asp Glu Ala Leu Ala Ile Ala Ala Leu Glu Leu Leu

35 40 45

Pro Arg Glu Leu Phe Pro Pro Leu Phe Met Ala Ala Phe Asp Gly Arg

50 55 60

His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys

65 70 75 80

Leu Pro Leu Gly Val Leu Met Lys Gly Gln His Leu His Leu Glu Thr

85 90 95

Phe Lys Ala Val Leu Asp Gly Leu Asp Val Leu Leu Ala Gln Glu Val

100 105 110

Arg Pro Arg Arg Trp Lys Leu Gln Val Leu Asp Leu Arg Lys Asn Ser

115 120 125

His Gln Asp Phe Trp Thr Val Trp Ser Gly Asn Arg Ala Ser Leu Tyr

130 135 140

Ser Phe Pro Glu Pro Glu Ala Ala Gln Pro Met Thr Lys Lys Arg Lys

145 150 155 160

Val Asp Gly Leu Ser Thr Glu Ala Glu Gln Pro Phe Ile Pro Val Glu

165 170 175

Val Leu Val Asp Leu Phe Leu Lys Glu Gly Ala Cys Asp Glu Leu Phe

180 185 190

Ser Tyr Leu Ile Glu Lys Val Lys Arg Lys Lys Asn Val Leu Arg Leu

195 200 205

Cys Cys Lys Lys Leu Lys Ile Phe Ala Met Pro Met Gln Asp Ile Lys

210 215 220

Met Ile Leu Lys Met Val Gln Leu Asp Ser Ile Glu Asp Leu Glu Val

225 230 235 240

Thr Cys Thr Trp Lys Leu Pro Thr Leu Ala Lys Phe Ser Pro Tyr Leu

245 250 255

Gly Gln Met Ile Asn Leu Arg Arg Leu Leu Leu Ser His Ile His Ala

260 265 270

Ser Ser Tyr Ile Ser Pro Glu Lys Glu Glu Gln Tyr Ile Ala Gln Phe

275 280 285

Thr Ser Gln Phe Leu Ser Leu Gln Cys Leu Gln Ala Leu Tyr Val Asp

290 295 300

Ser Leu Phe Phe Leu Arg Gly Arg Leu Asp Gln Leu Leu Arg His Val

305 310 315 320

Met Asn Pro Leu Glu Thr Leu Ser Ile Thr Asn Cys Arg Leu Ser Glu

325 330 335

Gly Asp Val Met His Leu Ser Gln Ser Pro Ser Val Ser Gln Leu Ser

340 345 350

Val Leu Ser Leu Ser Gly Val Met Leu Thr Asp Val Ser Pro Glu Pro

355 360 365

Leu Gln Ala Leu Leu Glu Arg Ala Ser Ala Thr Leu Gln Asp Leu Val

370 375 380

Phe Asp Glu Cys Gly Ile Thr Asp Asp Gln Leu Leu Ala Leu Leu Pro

385 390 395 400

Ser Leu Ser His Cys Ser Gln Leu Thr Thr Leu Ser Phe Tyr Gly Asn

405 410 415

Ser Ile Ser Ile Ser Ala Leu Gln Ser Leu Leu Gln His Leu Ile Gly

420 425 430

Leu Ser Asn Leu Thr His Val Leu Tyr Pro Val Pro Leu Glu Ser Tyr

435 440 445

Glu Asp Ile His Gly Thr Leu His Leu Glu Arg Leu Ala Tyr Leu His

450 455 460

Ala Arg Leu Arg Glu Leu Leu Cys Glu Leu Gly Arg Pro Ser Met Val

465 470 475 480

Trp Leu Ser Ala Asn Pro Cys Pro His Cys Gly Asp Arg Thr Phe Tyr

485 490 495

Asp Pro Glu Pro Ile Leu Cys Pro Cys Phe Met Pro Asn

500 505

<210> 151

<211> 315

<212> PRT

<213> Artificial sequence

<220>

<223> MAGE-A9 antigen

<400> 151

Met Ser Leu Glu Gln Arg Ser Pro His Cys Lys Pro Asp Glu Asp Leu

1 5 10 15

Glu Ala Gln Gly Glu Asp Leu Gly Leu Met Gly Ala Gln Glu Pro Thr

20 25 30

Gly Glu Glu Glu Glu Thr Thr Ser Ser Ser Asp Ser Lys Glu Glu Glu

35 40 45

Val Ser Ala Ala Gly Ser Ser Ser Pro Pro Gln Ser Pro Gln Gly Gly

50 55 60

Ala Ser Ser Ser Ile Ser Val Tyr Tyr Thr Leu Trp Ser Gln Phe Asp

65 70 75 80

Glu Gly Ser Ser Ser Gln Glu Glu Glu Glu Pro Ser Ser Ser Val Asp

85 90 95

Pro Ala Gln Leu Glu Phe Met Phe Gln Glu Ala Leu Lys Leu Lys Val

100 105 110

Ala Glu Leu Val His Phe Leu Leu His Lys Tyr Arg Val Lys Glu Pro

115 120 125

Val Thr Lys Ala Glu Met Leu Glu Ser Val Ile Lys Asn Tyr Lys Arg

130 135 140

Tyr Phe Pro Val Ile Phe Gly Lys Ala Ser Glu Phe Met Gln Val Ile

145 150 155 160

Phe Gly Thr Asp Val Lys Glu Val Asp Pro Ala Gly His Ser Tyr Ile

165 170 175

Leu Val Thr Ala Leu Gly Leu Ser Cys Asp Ser Met Leu Gly Asp Gly

180 185 190

His Ser Met Pro Lys Ala Ala Leu Leu Ile Ile Val Leu Gly Val Ile

195 200 205

Leu Thr Lys Asp Asn Cys Ala Pro Glu Glu Val Ile Trp Glu Ala Leu

210 215 220

Ser Val Met Gly Val Tyr Val Gly Lys Glu His Met Phe Tyr Gly Glu

225 230 235 240

Pro Arg Lys Leu Leu Thr Gln Asp Trp Val Gln Glu Asn Tyr Leu Glu

245 250 255

Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala His Tyr Glu Phe Leu Trp

260 265 270

Gly Ser Lys Ala His Ala Glu Thr Ser Tyr Glu Lys Val Ile Asn Tyr

275 280 285

Leu Val Met Leu Asn Ala Arg Glu Pro Ile Cys Tyr Pro Ser Leu Tyr

290 295 300

Glu Glu Val Leu Gly Glu Glu Gln Glu Gly Val

305 310 315

<210> 152

<211> 313

<212> PRT

<213> Artificial sequence

<220>

<223> HOME-TES-85

<400> 152

Met Ala Ser Phe Arg Lys Leu Thr Leu Ser Glu Lys Val Pro Pro Asn

1 5 10 15

His Pro Ser Arg Lys Lys Val Asn Phe Leu Asp Met Ser Leu Asp Asp

20 25 30

Ile Ile Ile Tyr Lys Glu Leu Glu Gly Thr Asn Ala Glu Glu Glu Lys

35 40 45

Asn Lys Arg Gln Asn His Ser Lys Lys Glu Ser Pro Ser Arg Gln Gln

50 55 60

Ser Lys Ala His Arg His Arg His Arg Arg Gly Tyr Ser Arg Cys Arg

65 70 75 80

Ser Asn Ser Glu Glu Gly Asn His Asp Lys Lys Pro Ser Gln Lys Pro

85 90 95

Ser Gly Phe Lys Ser Gly Gln His Pro Leu Asn Gly Gln Pro Leu Ile

100 105 110

Glu Gln Glu Lys Cys Ser Asp Asn Tyr Glu Ala Gln Ala Glu Lys Asn

115 120 125

Gln Gly Gln Ser Glu Gly Asn Gln His Gln Ser Glu Gly Asn Pro Asp

130 135 140

Lys Ser Glu Glu Ser Gln Gly Gln Pro Glu Glu Asn His His Ser Glu

145 150 155 160

Arg Ser Arg Asn His Leu Glu Arg Ser Leu Ser Gln Ser Asp Arg Ser

165 170 175

Gln Gly Gln Leu Lys Arg His His Pro Gln Tyr Glu Arg Ser His Gly

180 185 190

Gln Tyr Lys Arg Ser His Gly Gln Ser Glu Arg Ser His Gly His Ser

195 200 205

Glu Arg Ser His Gly His Ser Glu Arg Ser His Gly His Ser Glu Arg

210 215 220

Ser His Gly His Ser Lys Arg Ser Arg Ser Gln Gly Asp Leu Val Asp

225 230 235 240

Thr Gln Ser Asp Leu Ile Ala Thr Gln Arg Asp Leu Ile Ala Thr Gln

245 250 255

Lys Asp Leu Ile Ala Thr Gln Arg Asp Leu Ile Ala Thr Gln Arg Asp

260 265 270

Leu Ile Val Thr Gln Arg Asp Leu Val Ala Thr Glu Arg Asp Leu Ile

275 280 285

Asn Gln Ser Gly Arg Ser His Gly Gln Ser Glu Arg His Gln Arg Tyr

290 295 300

Ser Thr Gly Lys Asn Thr Ile Thr Thr

305 310

<210> 153

<211> 385

<212> PRT

<213> Artificial sequence

<220>

<223> TSP50 antigen

<400> 153

Met Gly Arg Trp Cys Gln Thr Val Ala Arg Gly Gln Arg Pro Arg Thr

1 5 10 15

Ser Ala Pro Ser Arg Ala Gly Ala Leu Leu Leu Leu Leu Leu Leu Leu

20 25 30

Arg Ser Ala Gly Cys Trp Gly Ala Gly Glu Ala Pro Gly Ala Leu Ser

35 40 45

Thr Ala Asp Pro Ala Asp Gln Ser Val Gln Cys Val Pro Lys Ala Thr

50 55 60

Cys Pro Ser Ser Arg Pro Arg Leu Leu Trp Gln Thr Pro Thr Thr Gln

65 70 75 80

Thr Leu Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly

85 90 95

Lys Val Asp Pro Tyr Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro

100 105 110

Thr Leu Arg Asp Pro Glu Ala Val Ala Arg Arg Trp Pro Trp Met Val

115 120 125

Ser Val Arg Ala Asn Gly Thr His Ile Cys Ala Gly Thr Ile Ile Ala

130 135 140

Ser Gln Trp Val Leu Thr Val Ala His Cys Leu Ile Trp Arg Asp Val

145 150 155 160

Ile Tyr Ser Val Arg Val Gly Ser Pro Trp Ile Asp Gln Met Thr Gln

165 170 175

Thr Ala Ser Asp Val Pro Val Leu Gln Val Ile Met His Ser Arg Tyr

180 185 190

Arg Ala Gln Arg Phe Trp Ser Trp Val Gly Gln Ala Asn Asp Ile Gly

195 200 205

Leu Leu Lys Leu Lys Gln Glu Leu Lys Tyr Ser Asn Tyr Val Arg Pro

210 215 220

Ile Cys Leu Pro Gly Thr Asp Tyr Val Leu Lys Asp His Ser Arg Cys

225 230 235 240

Thr Val Thr Gly Trp Gly Leu Ser Lys Ala Asp Gly Met Trp Pro Gln

245 250 255

Phe Arg Thr Ile Gln Glu Lys Glu Val Ile Ile Leu Asn Asn Lys Glu

260 265 270

Cys Asp Asn Phe Tyr His Asn Phe Thr Lys Ile Pro Thr Leu Val Gln

275 280 285

Ile Ile Lys Ser Gln Met Met Cys Ala Glu Asp Thr His Arg Glu Lys

290 295 300

Phe Cys Tyr Glu Leu Thr Gly Glu Pro Leu Val Cys Ser Met Glu Gly

305 310 315 320

Thr Trp Tyr Leu Val Gly Leu Val Ser Trp Gly Ala Gly Cys Gln Lys

325 330 335

Ser Glu Ala Pro Pro Ile Tyr Leu Gln Val Ser Ser Tyr Gln His Trp

340 345 350

Ile Trp Asp Cys Leu Asn Gly Gln Ala Leu Ala Leu Pro Ala Pro Ser

355 360 365

Arg Thr Leu Leu Leu Ala Leu Pro Leu Pro Leu Ser Leu Leu Ala Ala

370 375 380

Leu

385

<210> 154

<211> 314

<212> PRT

<213> Artificial sequence

<220>

<223> EpCAM antigen

<400> 154

Met Ala Pro Pro Gln Val Leu Ala Phe Gly Leu Leu Leu Ala Ala Ala

1 5 10 15

Thr Ala Thr Phe Ala Ala Ala Gln Glu Glu Cys Val Cys Glu Asn Tyr

20 25 30

Lys Leu Ala Val Asn Cys Phe Val Asn Asn Asn Arg Gln Cys Gln Cys

35 40 45

Thr Ser Val Gly Ala Gln Asn Thr Val Ile Cys Ser Lys Leu Ala Ala

50 55 60

Lys Cys Leu Val Met Lys Ala Glu Met Asn Gly Ser Lys Leu Gly Arg

65 70 75 80

Arg Ala Lys Pro Glu Gly Ala Leu Gln Asn Asn Asp Gly Leu Tyr Asp

85 90 95

Pro Asp Cys Asp Glu Ser Gly Leu Phe Lys Ala Lys Gln Cys Asn Gly

100 105 110

Thr Ser Met Cys Trp Cys Val Asn Thr Ala Gly Val Arg Arg Thr Asp

115 120 125

Lys Asp Thr Glu Ile Thr Cys Ser Glu Arg Val Arg Thr Tyr Trp Ile

130 135 140

Ile Ile Glu Leu Lys His Lys Ala Arg Glu Lys Pro Tyr Asp Ser Lys

145 150 155 160

Ser Leu Arg Thr Ala Leu Gln Lys Glu Ile Thr Thr Arg Tyr Gln Leu

165 170 175

Asp Pro Lys Phe Ile Thr Ser Ile Leu Tyr Glu Asn Asn Val Ile Thr

180 185 190

Ile Asp Leu Val Gln Asn Ser Ser Gln Lys Thr Gln Asn Asp Val Asp

195 200 205

Ile Ala Asp Val Ala Tyr Tyr Tyr Phe Glu Lys Asp Val Lys Gly Glu Ser

210 215 220

Leu Phe His Ser Lys Lys Met Asp Leu Thr Val Asn Gly Glu Gln Leu

225 230 235 240

Asp Leu Asp Pro Gly Gln Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala

245 250 255

Pro Glu Phe Ser Met Gln Gly Leu Lys Ala Gly Val Ile Ala Val Ile

260 265 270

Val Val Val Val Ile Ala Val Val Ala Gly Ile Val Val Leu Val Ile

275 280 285

Ser Arg Lys Lys Arg Met Ala Lys Tyr Glu Lys Ala Glu Ile Lys Glu

290 295 300

Met Gly Glu Met His Arg Glu Leu Asn Ala

305 310

<210> 155

<211> 777

<212> PRT

<213> Artificial sequence

<220>

<223> CAGE1 antigen

<400> 155

Met Asn Lys Asp Tyr Gln Lys Phe Trp Ser Ser Pro Ser Asp Pro Val

1 5 10 15

His Phe Glu Val Asp Thr Ser His Glu Lys Val Glu Ser Met Ser Glu

20 25 30

Ser Asp Thr Met Asn Val Ser Asn Leu Ser Gln Gly Val Met Leu Ser

35 40 45

His Ser Pro Ile Cys Met Glu Thr Thr Gly Thr Thr Cys Asp Leu Pro

50 55 60

Gln Asn Glu Ile Lys Asn Phe Glu Arg Glu Asn Glu Tyr Glu Ser Thr

65 70 75 80

Leu Cys Glu Asp Ala Tyr Gly Thr Leu Asp Asn Leu Leu Asn Asp Asn

85 90 95

Asn Ile Glu Asn Tyr Ser Thr Asn Ala Leu Ile Gln Pro Val Asp Thr

100 105 110

Ile Ser Ile Ser Ser Leu Arg Gln Phe Glu Thr Val Cys Lys Phe His

115 120 125

Trp Val Glu Ala Phe Asp Asp Glu Met Thr Glu Lys Pro Glu Phe Gln

130 135 140

Ser Gln Val Tyr Asn Tyr Ala Lys Asp Asn Asn Ile Lys Gln Asp Ser

145 150 155 160

Phe Lys Glu Glu Asn Pro Met Glu Thr Ser Val Ser Ala Asn Thr Asp

165 170 175

Gln Leu Gly Asn Glu Tyr Phe Arg Gln Pro Pro Pro Arg Ser Pro Pro

180 185 190

Leu Ile His Cys Ser Gly Glu Met Leu Lys Phe Thr Glu Lys Ser Leu

195 200 205

Ala Lys Ser Ile Ala Lys Glu Ser Ala Leu Asn Pro Ser Gln Pro Pro

210 215 220

Ser Phe Leu Cys Lys Thr Ala Val Pro Ser Lys Glu Ile Gln Asn Tyr

225 230 235 240

Gly Glu Ile Pro Glu Met Ser Val Ser Tyr Glu Lys Glu Val Thr Ala

245 250 255

Glu Gly Val Glu Arg Pro Glu Ile Val Ser Thr Trp Ser Ser Ala Gly

260 265 270

Ile Ser Trp Arg Ser Glu Ala Cys Arg Glu Asn Cys Glu Met Pro Asp

275 280 285

Trp Glu Gln Ser Ala Glu Ser Leu Gln Pro Val Gln Glu Asp Met Ala

290 295 300

Leu Asn Glu Val Leu Gln Lys Leu Lys His Thr Asn Arg Lys Gln Glu

305 310 315 320

Val Arg Ile Gln Glu Leu Gln Cys Ser Asn Leu Tyr Leu Glu Lys Arg

325 330 335

Val Lys Glu Leu Gln Met Lys Ile Thr Lys Gln Gln Val Phe Ile Asp

340 345 350

Val Ile Asn Lys Leu Lys Glu Asn Val Glu Glu Leu Ile Glu Asp Lys

355 360 365

Tyr Lys Ile Ile Leu Glu Lys Asn Asp Thr Lys Lys Thr Leu Gln Asn

370 375 380

Leu Glu Glu Val Leu Ala Asn Thr Gln Lys His Leu Gln Glu Ser Arg

385 390 395 400

Asn Asp Lys Glu Met Leu Gln Leu Gln Phe Lys Lys Ile Lys Ala Asn

405 410 415

Tyr Val Cys Leu Gln Glu Arg Tyr Met Thr Glu Met Gln Gln Lys Asn

420 425 430

Lys Ser Val Ser Gln Tyr Leu Glu Met Asp Lys Thr Leu Ser Lys Lys

435 440 445

Glu Glu Glu Val Glu Arg Leu Gln Gln Leu Lys Lys Glu Leu Glu Lys

450 455 460

Ala Thr Ala Ser Ala Leu Asp Leu Leu Lys Arg Glu Lys Glu Ala Gln

465 470 475 480

Glu Gln Glu Phe Leu Ser Leu Gln Glu Glu Phe Gln Lys Leu Glu Lys

485 490 495

Glu Asn Leu Glu Glu Arg Gln Lys Leu Lys Ser Arg Leu Glu Lys Leu

500 505 510

Leu Thr Gln Val Arg Asn Leu Gln Phe Met Ser Glu Asn Glu Arg Thr

515 520 525

Lys Asn Ile Lys Leu Gln Gln Gln Ile Asn Glu Val Lys Asn Glu Asn

530 535 540

Ala Lys Leu Lys Gln Gln Val Ala Arg Ser Glu Glu Gln Asn Tyr Val

545 550 555 560

Pro Lys Phe Glu Thr Ala Gln Leu Lys Asp Gln Leu Glu Glu Val Leu

565 570 575

Lys Ser Asp Ile Thr Lys Asp Thr Lys Thr Thr His Ser Asn Leu Leu

580 585 590

Pro Asp Cys Ser Pro Cys Glu Glu Arg Leu Asn Pro Ala Asp Ile Lys

595 600 605

Arg Ala Ser Gln Leu Ala Ser Lys Met His Ser Leu Leu Ala Leu Met

610 615 620

Val Gly Leu Leu Thr Cys Gln Asp Ile Ile Asn Ser Asp Ala Glu His

625 630 635 640

Phe Lys Glu Ser Glu Lys Val Ser Asp Ile Met Leu Gln Lys Leu Lys

645 650 655

Ser Leu His Leu Lys Lys Lys Thr Leu Asp Lys Glu Val Ile Asp Cys

660 665 670

Asp Ser Asp Glu Ala Lys Ser Ile Arg Asp Val Pro Thr Leu Leu Gly

675 680 685

Ala Lys Leu Asp Lys Tyr His Ser Leu Asn Glu Glu Leu Asp Phe Leu

690 695 700

Val Thr Ser Tyr Glu Glu Ile Ile Glu Cys Ala Asp Gln Arg Leu Ala

705 710 715 720

Ile Ser His Ser Gln Ile Ala His Leu Glu Glu Arg Asn Lys His Leu

725 730 735

Glu Asp Leu Ile Arg Lys Pro Arg Glu Lys Ala Arg Lys Pro Arg Ser

740 745 750

Lys Ser Leu Glu Asn His Pro Lys Ser Met Thr Met Met Pro Ala Leu

755 760 765

Phe Lys Glu Asn Arg Asn Asp Leu Asp

770 775

<210> 156

<211> 442

<212> PRT

<213> Artificial sequence

<220>

<223> FBXO39 antigen

<400> 156

Met Asp Glu Glu Ser Glu Leu Ile Gln Pro Gln Asp Gln Ser Cys Trp

1 5 10 15

Ala Phe Leu Pro Asp Leu Cys Leu Cys Arg Val Phe Trp Trp Leu Gly

20 25 30

Asp Arg Asp Arg Ser Arg Ala Ala Leu Val Cys Arg Lys Trp Asn Gln

35 40 45

Met Met Tyr Ser Ala Glu Leu Trp Arg Tyr Arg Thr Ile Thr Phe Ser

50 55 60

Gly Arg Pro Ser Arg Val His Ala Ser Glu Val Glu Ser Ala Val Trp

65 70 75 80

Tyr Val Lys Lys Phe Gly Arg Tyr Leu Glu His Leu Glu Val Lys Phe

85 90 95

Met Asn Pro Tyr Asn Ala Val Leu Thr Lys Lys Phe Gln Val Thr Met

100 105 110

Arg Gly Leu Leu Ser Cys Leu Ser Lys Ser Asn Asn Arg Leu Lys Ser

115 120 125

Leu Ser Ile Gln Tyr Leu Glu Leu Asp Arg Leu Val Trp Arg Asn Ser

130 135 140

Ile Arg Ser Ser Phe Ile Ser Ser Leu Ser Phe Phe Leu Lys Lys Met

145 150 155 160

Gly Lys Arg Leu Asp Tyr Leu Asn Leu Lys Gly Ala Arg Leu Thr Val

165 170 175

Glu Gln Gly Cys Gln Ile Leu Asp Ser Leu Ser Tyr Met Arg Asn Glu

180 185 190

Asn Val Ile Ser Glu Leu Asn Ile Glu Asp Tyr Phe Ser His His Leu

195 200 205

Ala Val Tyr Asn Ser Pro Gln Phe Lys Lys Thr Met Ser Thr Phe His

210 215 220

Asn Leu Val Ser Leu Asn Leu Asn Tyr Asn Cys Ile Ser Asp Glu Leu

225 230 235 240

Leu Glu Asn Leu Cys Glu Asn Ala Ser Thr Leu Arg Thr Ile Asn Ile

245 250 255

Lys Cys His Val His Asp Pro His Gly Gln Val Ile Trp Gly Met Ser

260 265 270

Trp Ala Lys Leu Ala Arg Gln Ala Thr Asn Leu Lys Val Asn Phe Phe

275 280 285

Phe Glu Arg Ile Met Lys Tyr Glu Arg Leu Ala Arg Ile Leu Leu Gln

290 295 300

Glu Ile Pro Ile Arg Ser Ile Ser Leu Arg Ser Cys Tyr Phe Ser Asp

305 310 315 320

Pro Asp Cys Ser Met Arg Pro Thr Leu Ile Asp Leu Leu Pro Thr Phe

325 330 335

Arg His Thr Leu Gln Lys Leu Thr Cys Glu Phe Asn Asn Asn His Glu

340 345 350

Ser Leu Asp Glu Glu Leu His Leu Leu Ile Ile Ser Cys Arg Lys Leu

355 360 365

Phe Tyr Phe Lys Ile Trp Ala Phe Leu Asp Val Ser Phe Val Glu Arg

370 375 380

Ile Leu Lys Ser Gln Lys Glu Arg Gln Cys Ala Leu Arg Val Phe Lys

385 390 395 400

Ala Arg Ile Tyr Thr Asn Arg Tyr Glu Thr Asn Glu Glu Asp Lys Thr

405 410 415

Leu Gln Glu Ile Tyr Arg Lys Tyr Arg Lys Leu Ile Glu Ser Glu Leu

420 425 430

Ser Tyr Phe Val Ile Val Tyr Ser Val Met

435 440

<210> 157

<211> 318

<212> PRT

<213> Artificial sequence

<220>

<223> MAGE-A8

<400> 157

Met Leu Leu Gly Gln Lys Ser Gln Arg Tyr Lys Ala Glu Glu Gly Leu

1 5 10 15

Gln Ala Gln Gly Glu Ala Pro Gly Leu Met Asp Val Gln Ile Pro Thr

20 25 30

Ala Glu Glu Gln Lys Ala Ala Ser Ser Ser Ser Ser Thr Leu Ile Met Gly

35 40 45

Thr Leu Glu Glu Val Thr Asp Ser Gly Ser Pro Ser Pro Pro Gln Ser

50 55 60

Pro Glu Gly Ala Ser Ser Ser Leu Thr Val Thr Asp Ser Thr Leu Trp

65 70 75 80

Ser Gln Ser Asp Glu Gly Ser Ser Ser Asn Glu Glu Glu Gly Pro Ser

85 90 95

Thr Ser Pro Asp Pro Ala His Leu Glu Ser Leu Phe Arg Glu Ala Leu

100 105 110

Asp Glu Lys Val Ala Glu Leu Val Arg Phe Leu Leu Arg Lys Tyr Gln

115 120 125

Ile Lys Glu Pro Val Thr Lys Ala Glu Met Leu Glu Ser Val Ile Lys

130 135 140

Asn Tyr Lys Asn His Phe Pro Asp Ile Phe Ser Lys Ala Ser Glu Cys

145 150 155 160

Met Gln Val Ile Phe Gly Ile Asp Val Lys Glu Val Asp Pro Ala Gly

165 170 175

His Ser Tyr Ile Leu Val Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu

180 185 190

Leu Gly Asp Asp Gln Ser Thr Pro Lys Thr Gly Leu Leu Ile Ile Val

195 200 205

Leu Gly Met Ile Leu Met Glu Gly Ser Arg Ala Pro Glu Glu Ala Ile

210 215 220

Trp Glu Ala Leu Ser Val Met Gly Leu Tyr Asp Gly Arg Glu His Ser

225 230 235 240

Val Tyr Trp Lys Leu Arg Lys Leu Leu Thr Gln Glu Trp Val Gln Glu

245 250 255

Asn Tyr Leu Glu Tyr Arg Gln Ala Pro Gly Ser Asp Pro Val Arg Tyr

260 265 270

Glu Phe Leu Trp Gly Pro Arg Ala Leu Ala Glu Thr Ser Tyr Val Lys

275 280 285

Val Leu Glu His Val Val Arg Val Asn Ala Arg Val Arg Ile Ser Tyr

290 295 300

Pro Ser Leu His Glu Glu Ala Leu Gly Glu Glu Lys Gly Val

305 310 315

<210> 158

<211> 314

<212> PRT

<213> Artificial sequence

<220>

<223> MAGE-A6 antigen

<400> 158

Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu

1 5 10 15

Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala

20 25 30

Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val

35 40 45

Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser

50 55 60

Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp

65 70 75 80

Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser

85 90 95

Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys

100 105 110

Val Ala Lys Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu

115 120 125

Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln

130 135 140

Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Asp Ser Leu Gln Leu

145 150 155 160

Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Val Tyr

165 170 175

Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp

180 185 190

Asn Gln Ile Met Pro Lys Thr Gly Phe Leu Ile Ile Ile Leu Ala Ile

195 200 205

Ile Ala Lys Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu

210 215 220

Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Phe Gly

225 230 235 240

Asp Pro Lys Lys Leu Leu Thr Gln Tyr Phe Val Gln Glu Asn Tyr Leu

245 250 255

Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu

260 265 270

Trp Gly Pro Arg Ala Leu Ile Glu Thr Ser Tyr Val Lys Val Leu His

275 280 285

His Met Val Lys Ile Ser Gly Gly Pro Arg Ile Ser Tyr Pro Leu Leu

290 295 300

His Glu Trp Ala Leu Arg Glu Gly Glu Glu

305 310

<210> 159

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 1

<400> 159

Met Met Asn Leu Met Gln Pro Lys Thr Gln Gln Thr Tyr Thr Tyr Asp

1 5 10 15

<210> 160

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 2

<400> 160

Gly Arg Gly Ser Thr Thr Thr Asn Tyr Leu Leu Asp Arg Asp Asp Tyr

1 5 10 15

Arg Asn Thr Ser Asp

20

<210> 161

<211> 22

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 3

<400> 161

Leu Lys Lys Gly Ala Ala Asp Gly Gly Lys Leu Asp Gly Asn Ala Lys

1 5 10 15

Leu Asn Arg Ser Leu Lys

20

<210> 162

<211> 22

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 4

<400> 162

Phe Pro Pro Lys Asp Asp His Thr Leu Lys Phe Leu Tyr Asp Asp Asn

1 5 10 15

Gln Arg Pro Tyr Pro Pro

20

<210> 163

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<223> Additional Peptide 5

<400> 163

Arg Tyr Arg Lys Pro Asp Tyr Thr Leu Asp Asp Gly His Gly Leu Leu

1 5 10 15

Arg Phe Lys Ser Thr

20

<210> 164

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Additional Peptide 6

<400> 164

Gln Arg Pro Pro Phe Ser Gln Leu His Arg Phe Leu Ala Asp Ala Leu

1 5 10 15

Asn Thr

<210> 165

<211> 25

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 7

<400> 165

Ala Leu Asp Gln Cys Lys Thr Ser Cys Ala Leu Met Gln Gln His Tyr

1 5 10 15

Asp Gln Thr Ser Cys Phe Ser Ser Pro

20 25

<210> 166

<211> 25

<212> PRT

<213> Artificial sequence

<220>

<223> Additional Peptide 8

<400> 166

Ser Thr Ala Pro Pro Ala His Gly Val Thr Ser Ala Pro Asp Thr Arg

1 5 10 15

Pro Ala Pro Gly Ser Thr Ala Pro Pro

20 25

<210> 167

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 9

<400> 167

Tyr Leu Glu Pro Gly Pro Val Thr Ala

1 5

<210> 168

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 10

<400> 168

Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr

1 5 10 15

Val Leu Thr Val Val

20

<210> 169

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 11

<400> 169

Ser Ser Lys Ala Leu Gln Arg Pro Val

1 5

<210> 170

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 12

<400> 170

Arg Met Phe Pro Asn Ala Pro Tyr Leu

1 5

<210> 171

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Additional peptide 13

<400> 171

Arg Met Phe Pro Asn Ala Pro Tyr Leu

1 5

<210> 172

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 41

<400> 172

Phe Val Ala Ser Ile Asn Leu Thr Leu

1 5

<210> 173

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 42

<400> 173

Phe Tyr Asp Pro Thr Ser Ala Met Val

1 5

<210> 174

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 43

<400> 174

Arg Thr Tyr Trp Ile Ile Ile Glu Leu

1 5

<210> 175

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 45

<400> 175

His Ala Phe Asp Gly Thr Ile Leu Phe

1 5

<210> 176

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 46

<400> 176

Phe Gln Met Pro His Gln Glu Ile Val

1 5

<210> 177

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 47

<400> 177

Leu Gln Tyr Glu Asn Ser Ile Met Leu

1 5

<210> 178

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 48

<400> 178

Tyr Thr Leu Asp Asp Leu Tyr Pro Met

1 5

<210> 179

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 49

<400> 179

Asn Ala Tyr His Met Ser Ser Thr Met

1 5

<210> 180

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 50

<400> 180

Val Gln Phe Glu Lys Val Ser Ala Leu

1 5

<210> 181

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 51

<400> 181

Arg Thr Ser Tyr Leu His Ser Pro Phe

1 5

<210> 182

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 52

<400> 182

Phe Gln Trp Arg Ile Thr His Ser Phe

1 5

<210> 183

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 53

<400> 183

Phe Ala Ala Ala Tyr Phe Glu Ser Leu

1 5

<210> 184

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 54

<400> 184

Tyr Val Asn Arg Leu Ser Ser Leu Val

1 5

<210> 185

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 55

<400> 185

Arg Leu Leu Ser Ser Thr Leu Ser Leu

1 5

<210> 186

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 56

<400> 186

Tyr Thr Phe Glu Gly Ala Arg Tyr Tyr

1 5

<210> 187

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 57

<400> 187

Lys Ala Met Ala Arg Leu Gln Glu Leu

1 5

<210> 188

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 58

<400> 188

Phe Val Ala Ser Ile Asn Glu Gly Met Thr

1 5 10

<210> 189

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 59

<400> 189

Tyr Ala Val His Pro Met Ser Pro Val

1 5

<210> 190

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 60

<400> 190

Met Gln Met Phe Gly Leu Gly Ala Ile

1 5

<210> 191

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 61

<400> 191

Tyr Val Asp Glu Lys Ala Pro Glu Phe

1 5

<210> 192

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 62

<400> 192

His Ser Tyr Val Leu Val Thr Ser Leu

1 5

<210> 193

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 63

<400> 193

Arg Leu Leu Glu Phe Tyr Leu Ala Met

1 5

<210> 194

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 64

<400> 194

Leu Ala Met Pro Phe Ala Thr Pro Met

1 5

<210> 195

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 41

<400> 195

Phe Val Ala Ser Ile Asn Leu Thr Leu Thr Lys Trp Tyr Ser Arg

1 5 10 15

<210> 196

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 42

<400> 196

Arg Asn Phe Tyr Asp Pro Thr Ser Ala Met Val Leu Gln Gln His

1 5 10 15

<210> 197

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 43

<400> 197

Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg Leu

1 5 10 15

<210> 198

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 44

<400> 198

Arg Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Glu

1 5 10 15

<210> 199

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 46

<400> 199

Val Cys Met Phe Thr Ser Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His

1 5 10 15

<210> 200

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 47

<400> 200

His Ala Phe Asp Gly Thr Ile Leu Phe Leu Pro Lys Arg Leu Gln

1 5 10 15

<210> 201

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 48

<400> 201

Ser Asp Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser

1 5 10 15

<210> 202

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 49

<400> 202

Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser

1 5 10 15

<210> 203

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 50

<400> 203

Tyr Ser Arg Val Val Phe Gln Met Pro His Gln Glu Ile Val Asp

1 5 10 15

<210> 204

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 51

<400> 204

Gly Phe Thr Thr Ser Ile Leu Gln Tyr Glu Asn Ser Ile Met Leu

1 5 10 15

<210> 205

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 52

<400> 205

Leu Arg Tyr Arg Tyr Thr Leu Asp Asp Leu Tyr Pro Met Met Asn

1 5 10 15

<210> 206

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 53

<400> 206

Tyr Ser Ser Asn Ala Tyr His Met Ser Ser Thr Met Lys Pro Asn

1 5 10 15

<210> 207

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 54

<400> 207

Leu Gln Lys Val Gln Phe Glu Lys Val Ser Ala Leu Ala Asp Leu

1 5 10 15

<210> 208

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 55

<400> 208

Asn Arg Thr Ser Tyr Leu His Ser Pro Phe Ser Thr Gly Arg Ser

1 5 10 15

<210> 209

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 56

<400> 209

Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala

1 5 10 15

<210> 210

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 57

<400> 210

Asn Ser Pro Leu Pro Phe Gln Trp Arg Ile Thr His Ser Phe Arg

1 5 10 15

<210> 211

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 58

<400> 211

Ala Phe Ala Ala Ala Tyr Phe Glu Ser Leu Leu Glu Lys Arg Glu

1 5 10 15

<210> 212

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 59

<400> 212

Asp Leu Ser Phe Tyr Val Asn Arg Leu Ser Ser Leu Val Ile Gln

1 5 10 15

<210> 213

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 60

<400> 213

Gln Asp Gly Arg Leu Leu Ser Ser Thr Leu Ser Leu Ser Ser Asn

1 5 10 15

<210> 214

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 61

<400> 214

Trp Glu Glu Ala Tyr Thr Phe Glu Gly Ala Arg Tyr Tyr Ile Asn

1 5 10 15

<210> 215

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 62

<400> 215

Glu Lys Ala Met Ala Arg Leu Gln Glu Leu Leu Thr Val Ser Glu

1 5 10 15

<210> 216

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 63

<400> 216

Arg Ser Ile Ala Gly Phe Val Ala Ser Ile Asn Glu Gly Met Thr

1 5 10 15

<210> 217

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 64

<400> 217

Ser Asp Tyr Ala Val His Pro Met Ser Pro Val Gly Arg Thr Ser

1 5 10 15

<210> 218

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 65

<400> 218

Met Met Gln Met Phe Gly Leu Gly Ala Ile Ser Leu Ile Leu Val

1 5 10 15

<210> 219

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 66

<400> 219

Leu Arg His Lys Cys Cys Phe Ser Ser Ser Gly Thr Thr Ser Phe

1 5 10 15

<210> 220

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 67

<400> 220

Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys

1 5 10 15

<210> 221

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 68

<400> 221

Gln Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser

1 5 10 15

<210> 222

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 69

<400> 222

Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Glu Asn Ala

1 5 10 15

<210> 223

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 70

<400> 223

Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser

1 5 10 15

<210> 224

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 71

<400> 224

Phe Met Phe Gln Glu Ala Leu Lys Leu Lys Val Ala Glu Leu Val

1 5 10 15

<210> 225

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 72

<400> 225

His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr

1 5 10 15

<210> 226

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 73

<400> 226

Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Thr Cys Leu

1 5 10 15

<210> 227

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 74

<400> 227

Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr Asp

1 5 10 15

<210> 228

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 75

<400> 228

Thr Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr

1 5 10 15

<210> 229

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 76

<400> 229

Ala Met Asp Ala Ile Phe Gly Ser Leu Ser Asp Glu Gly Ser Gly

1 5 10 15

<210> 230

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 77

<400> 230

Glu Ser Phe Ser Pro Thr Ala Met Asp Ala Ile Phe Gly Ser Leu

1 5 10 15

<210> 231

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 78

<400> 231

Lys Pro Ser Ala Phe Glu Pro Ala Thr Glu Met Gln Lys Ser Val

1 5 10 15

<210> 232

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 79

<400> 232

Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe Ala Thr Pro

1 5 10 15

<210> 233

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 80

<400> 233

Phe Tyr Leu Ala Met Pro Phe Ala Thr Pro Met Glu Ala Glu Leu

1 5 10 15

<210> 234

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 65

<400> 234

Cys Ser Met Glu Gly Thr Trp Tyr Leu

1 5

<210> 235

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 66

<400> 235

Leu Leu Ala Ala Ala Thr Ala Thr Phe

1 5

<210> 236

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 67

<400> 236

Phe Thr Val Cys Asn Ser His Val Leu

1 5

<210> 237

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 68

<400> 237

Leu Ala Leu Pro Leu Pro Leu Ser Leu

1 5

<210> 238

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 69

<400> 238

Arg Thr Leu Leu Leu Ala Leu Pro Leu

1 5

<210> 239

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 70

<400> 239

Phe Ile Ile Val Val Phe Val Tyr Leu

1 5

<210> 240

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 71

<400> 240

Leu Ala Ser Lys Met His Ser Leu Leu

1 5

<210> 241

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 72

<400> 241

Ser Ser Phe Ile Ser Ser Leu Ser Phe

1 5

<210> 242

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 73

<400> 242

Ser Thr Asn Ala Leu Ile Gln Pro Val

1 5

<210> 243

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 74

<400> 243

Thr Leu Pro Pro Ala Trp Gln Pro Phe

1 5

<210> 244

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 75

<400> 244

Arg Gln Phe Glu Thr Val Cys Lys Phe

1 5

<210> 245

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 76

<400> 245

Phe Ala Thr Cys Leu Gly Leu Ser Tyr

1 5

<210> 246

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 77

<400> 246

Phe Val Gln Glu Asn Tyr Leu Glu Tyr

1 5

<210> 247

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 78

<400> 247

Ala Ser Ser Ser Ser Thr Leu Ile Met

1 5

<210> 248

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 79

<400> 248

Tyr Ile Phe Ala Thr Cys Leu Gly Leu

1 5

<210> 249

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 80

<400> 249

Leu Pro Pro Ala Trp Gln Pro Phe Leu

1 5

<210> 250

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 81

<400> 250

Ile Ser Thr Phe Lys Asn Trp Pro Phe

1 5

<210> 251

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 81

<400> 251

Val Cys Ser Met Glu Gly Thr Trp Tyr Leu Val Gly Leu Val Ser

1 5 10 15

<210> 252

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 82

<400> 252

Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg Asp Pro Glu Ala

1 5 10 15

<210> 253

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 83

<400> 253

Tyr Arg Ser Cys Gly Phe Ser Tyr Glu Gln Asp Pro Thr Leu Arg

1 5 10 15

<210> 254

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 84

<400> 254

Leu Leu Ala Ala Ala Thr Ala Thr Phe Ala Ala Ala Gln Glu Glu

1 5 10 15

<210> 255

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 85

<400> 255

Lys Leu Gly Phe Ser Phe Val Arg Ile Thr Ala Leu Met Val Ser

1 5 10 15

<210> 256

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 86

<400> 256

Leu Pro Ser Thr Thr Met Glu Thr Gln Phe Pro Val Ser Glu Gly

1 5 10 15

<210> 257

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 87

<400> 257

Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu Cys Ile Ala

1 5 10 15

<210> 258

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 88

<400> 258

Gly Asn Ile Leu Asp Ser Phe Thr Val Cys Asn Ser His Val Leu

1 5 10 15

<210> 259

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 89

<400> 259

Gln Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser

1 5 10 15

<210> 260

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 90

<400> 260

Ser Arg Thr Leu Leu Leu Ala Leu Pro Leu Pro Leu Ser Leu Leu

1 5 10 15

<210> 261

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 91

<400> 261

Phe Ile Ile Val Val Phe Val Tyr Leu Thr Val Glu Asn Lys Ser

1 5 10 15

<210> 262

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 92

<400> 262

Arg Asn Ser Ile Arg Ser Ser Phe Ile Ser Ser Leu Ser Phe Phe

1 5 10 15

<210> 263

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 93

<400> 263

Asn Ile Glu Asn Tyr Ser Thr Asn Ala Leu Ile Gln Pro Val Asp

1 5 10 15

<210> 264

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 94

<400> 264

Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys

1 5 10 15

<210> 265

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 95

<400> 265

Arg Gln Phe Glu Thr Val Cys Lys Phe His Trp Val Glu Ala Phe

1 5 10 15

<210> 266

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 96

<400> 266

Pro Glu Glu Ala Ile Trp Glu Ala Leu Ser Val Met Gly Leu Tyr

1 5 10 15

<210> 267

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 97

<400> 267

Glu Lys Val Ala Glu Leu Val Arg Phe Leu Leu Arg Lys Tyr Gln

1 5 10 15

<210> 268

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 98

<400> 268

Lys Leu Leu Thr Gln Tyr Phe Val Gln Glu Asn Tyr Leu Glu Tyr

1 5 10 15

<210> 269

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 99

<400> 269

Ile Gly His Leu Tyr Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr

1 5 10 15

<210> 270

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 100

<400> 270

Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu Glu Tyr

1 5 10 15

<210> 271

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 101

<400> 271

Ala Ser Ser Ser Ser Thr Leu Ile Met Gly Thr Leu Glu Glu Val

1 5 10 15

<210> 272

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 82

<400> 272

Met Met Met Ser Ile Ala Thr Lys Ile

1 5

<210> 273

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 83

<400> 273

Lys Ala Phe Asp Gly Ala Ile Leu Phe

1 5

<210> 274

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 84

<400> 274

Arg Met Phe Pro Asn Ala Pro Tyr Leu

1 5

<210> 275

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 85

<400> 275

Arg Thr Tyr Trp Ile Ile Ile Glu Leu

1 5

<210> 276

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 86

<400> 276

Phe Thr Ser Ser Arg Met Ser Ser Phe

1 5

<210> 277

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 87

<400> 277

Tyr Leu Met Asn Arg Pro Gln Asn Leu

1 5

<210> 278

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 88

<400> 278

Met Ile Met Glu Asn Ile Gln Glu Leu

1 5

<210> 279

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 89

<400> 279

Met Met Ala Tyr Ser Asp Thr Thr Met

1 5

<210> 280

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 90

<400> 280

Phe Ala Ala Ala Tyr Phe Glu Ser Leu

1 5

<210> 281

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 91

<400> 281

Tyr Val Asp Pro Asp Val Gln Leu Val

1 5

<210> 282

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 92

<400> 282

Phe Val Ala Ser Ile Asn Leu Thr Leu

1 5

<210> 283

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 93

<400> 283

Tyr Ala Leu Gly Phe Gln His Ala Leu

1 5

<210> 284

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 94

<400> 284

Leu Gln Tyr Glu Asn Ser Ile Thr Leu

1 5

<210> 285

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 95

<400> 285

Lys Met Ser Ser Leu Leu Pro Thr Met

1 5

<210> 286

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 96

<400> 286

His Leu Gln Ser Val Thr Ala Pro Met

1 5

<210> 287

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 97

<400> 287

Phe Val Ala Ser Thr Asn Ala Glu Leu

1 5

<210> 288

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 98

<400> 288

Phe Tyr Asp Pro Thr Ser Ala Met Val

1 5

<210> 289

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 99

<400> 289

Met Ala Phe Val Thr Ser Gly Glu Leu

1 5

<210> 290

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 100

<400> 290

Tyr Val Asn Arg Leu Ser Ser Leu Val

1 5

<210> 291

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 101

<400> 291

Tyr Leu His Ala Arg Leu Arg Glu Leu

1 5

<210> 292

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 102

<400> 292

Phe Thr Gln Ser Gly Thr Met Lys Ile

1 5

<210> 293

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 103

<400> 293

His Ala Phe Asp Gly Thr Ile Leu Phe

1 5

<210> 294

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 104

<400> 294

Tyr Val Asp Glu Lys Ala Pro Glu Phe

1 5

<210> 295

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 105

<400> 295

Val Met Ser Glu Arg Val Ser Gly Leu

1 5

<210> 296

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 106

<400> 296

Leu Gln Tyr Glu Asn Ser Ile Met Leu

1 5

<210> 297

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 107

<400> 297

Phe Gln Met Pro His Gln Glu Ile Val

1 5

<210> 298

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 108

<400> 298

Lys Ala Met Val Gln Ala Trp Pro Phe

1 5

<210> 299

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 109

<400> 299

Arg Ala Ile Glu Gln Leu Ala Ala Met

1 5

<210> 300

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 110

<400> 300

Arg Ser Asp Glu Ile Val Leu Thr Val

1 5

<210> 301

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> 9mer T cell epitope 111

<400> 301

Tyr Ser Ser Asp Asn Leu Tyr Gln Met

1 5

<210> 302

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 102

<400> 302

Gln Gly Met Met Met Ser Ile Ala Thr Lys Ile Ala Met Gln Met

1 5 10 15

<210> 303

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 103

<400> 303

Lys Ala Lys Ala Phe Asp Gly Ala Ile Leu Phe Leu Ser Gln Lys

1 5 10 15

<210> 304

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 104

<400> 304

Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro

1 5 10 15

<210> 305

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 105

<400> 305

Arg Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Glu

1 5 10 15

<210> 306

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 106

<400> 306

Met Phe Thr Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His Met Lys

1 5 10 15

<210> 307

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 107

<400> 307

Gln Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg

1 5 10 15

<210> 308

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 108

<400> 308

Ser Thr Pro Met Ile Met Glu Asn Ile Gln Glu Leu Ile Arg Ser

1 5 10 15

<210> 309

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 109

<400> 309

Met Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp

1 5 10 15

<210> 310

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 110

<400> 310

Ala Phe Ala Ala Ala Tyr Phe Glu Ser Leu Leu Glu Lys Arg Glu

1 5 10 15

<210> 311

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 111

<400> 311

Arg Ala Ile Gln Gln Tyr Val Asp Pro Asp Val Gln Leu Val Met

1 5 10 15

<210> 312

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 112

<400> 312

Gly Phe Val Ala Ser Ile Asn Leu Thr Leu Thr Lys Trp Tyr Ser

1 5 10 15

<210> 313

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 113

<400> 313

Asp Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro

1 5 10 15

<210> 314

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 114

<400> 314

Gly Tyr Val Thr Ser Val Leu Gln Tyr Glu Asn Ser Ile Thr Leu

1 5 10 15

<210> 315

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 115

<400> 315

Val Arg Glu Glu Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met

1 5 10 15

<210> 316

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 116

<400> 316

Met Ser Leu Lys Gly His Leu Gln Ser Val Thr Ala Pro Met Gly

1 5 10 15

<210> 317

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 117

<400> 317

Gln Lys Ser Ile Ala Gly Phe Val Ala Ser Thr Asn Ala Glu Leu

1 5 10 15

<210> 318

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 118

<400> 318

Arg Asn Phe Tyr Asp Pro Thr Ser Ala Met Val Leu Gln Gln His

1 5 10 15

<210> 319

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 119

<400> 319

Asn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg

1 5 10 15

<210> 320

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 120

<400> 320

Leu Ser Phe Tyr Val Asn Arg Leu Ser Ser Leu Val Ile Gln Met

1 5 10 15

<210> 321

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 121

<400> 321

Leu Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu

1 5 10 15

<210> 322

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 122

<400> 322

Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys

1 5 10 15

<210> 323

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 123

<400> 323

His Ala Phe Asp Gly Thr Ile Leu Phe Leu Pro Lys Arg Leu Gln

1 5 10 15

<210> 324

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 124

<400> 324

Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser Met Gln Gly Leu Lys

1 5 10 15

<210> 325

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 125

<400> 325

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

1 5 10 15

<210> 326

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 126

<400> 326

Gly Phe Thr Thr Ser Ile Leu Gln Tyr Glu Asn Ser Ile Met Leu

1 5 10 15

<210> 327

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 127

<400> 327

Tyr Ser Arg Val Val Phe Gln Met Pro His Gln Glu Ile Val Asp

1 5 10 15

<210> 328

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 128

<400> 328

Arg His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe

1 5 10 15

<210> 329

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 129

<400> 329

Ala Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp

1 5 10 15

<210> 330

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 130

<400> 330

Glu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val

1 5 10 15

<210> 331

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> 15mer T cell epitope 131

<400> 331

Arg Thr Pro Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln

1 5 10 15

<210> 332

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 1

<400> 332

Ser Thr Pro Met Ile Met Glu Asn Ile Gln Glu Leu Ile Arg Ser Gln

1 5 10 15

Gly Met Met Met Ser Ile Ala Thr Lys Ile Ala Met Gln Met

20 25 30

<210> 333

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 2

<400> 333

Arg Asn Phe Tyr Asp Pro Thr Ser Ala Met Val Leu Gln Gln His Lys

1 5 10 15

Ala Lys Ala Phe Asp Gly Ala Ile Leu Phe Leu Ser Gln Lys

20 25 30

<210> 334

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 3

<400> 334

Asn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg Met

1 5 10 15

Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp

20 25 30

<210> 335

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 4

<400> 335

Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro Arg

1 5 10 15

Thr Pro Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln

20 25 30

<210> 336

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 5

<400> 336

Met Phe Thr Ser Ser Arg Met Ser Ser Ser Phe Asn Arg His Met Lys His

1 5 10 15

Ala Phe Asp Gly Thr Ile Leu Phe Leu Pro Lys Arg Leu Gln

20 25 30

<210> 337

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 6

<400> 337

Tyr Ser Arg Val Val Phe Gln Met Pro His Gln Glu Ile Val Asp Arg

1 5 10 15

Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Glu

20 25 30

<210> 338

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 7

<400> 338

Leu Ser Phe Tyr Val Asn Arg Leu Ser Ser Leu Val Ile Gln Met Arg

1 5 10 15

Ala Ile Gln Gln Tyr Val Asp Pro Asp Val Gln Leu Val Met

20 25 30

<210> 339

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 8

<400> 339

Gln Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg Ala

1 5 10 15

Phe Ala Ala Ala Tyr Phe Glu Ser Leu Leu Glu Lys Arg Glu

20 25 30

<210> 340

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 9

<400> 340

Gly Tyr Val Thr Ser Val Leu Gln Tyr Glu Asn Ser Ile Thr Leu Gln

1 5 10 15

Lys Ser Ile Ala Gly Phe Val Ala Ser Thr Asn Ala Glu Leu

20 25 30

<210> 341

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 10

<400> 341

Val Arg Glu Glu Ala Gln Lys Met Ser Ser Leu Leu Pro Thr Met Arg

1 5 10 15

Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys

20 25 30

<210> 342

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 11

<400> 342

Gly Phe Val Ala Ser Ile Asn Leu Thr Leu Thr Lys Trp Tyr Ser Tyr

1 5 10 15

Val Asp Glu Lys Ala Pro Glu Phe Ser Met Gln Gly Leu Lys

20 25 30

<210> 343

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 12

<400> 343

Met Ser Leu Lys Gly His Leu Gln Ser Val Thr Ala Pro Met Gly Ser

1 5 10 15

Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser

20 25 30

<210> 344

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 13

<400> 344

Asp Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Pro Leu

1 5 10 15

Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu

20 25 30

<210> 345

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 14

<400> 345

Gly Phe Thr Thr Ser Ile Leu Gln Tyr Glu Asn Ser Ile Met Leu Glu

1 5 10 15

Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val

20 25 30

<210> 346

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> Ovarian cancer vaccine peptide 15

<400> 346

Arg His Ser Gln Thr Leu Lys Ala Met Val Gln Ala Trp Pro Phe Ala

1 5 10 15

Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp

20 25 30

<210> 347

<211> 314

<212> PRT

<213> Artificial sequence

<220>

<223> MAGE-A3

<400> 347

Met Pro Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu

1 5 10 15

Glu Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala

20 25 30

Thr Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val

35 40 45

Thr Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser

50 55 60

Pro Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp

65 70 75 80

Ser Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser

85 90 95

Thr Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys

100 105 110

Val Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu

115 120 125

Pro Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln

130 135 140

Tyr Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu

145 150 155 160

Val Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr

165 170 175

Ile Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp

180 185 190

Asn Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile

195 200 205

Ile Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu

210 215 220

Leu Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly

225 230 235 240

Asp Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu

245 250 255

Glu Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu

260 265 270

Trp Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His

275 280 285

His Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu

290 295 300

His Glu Trp Val Leu Arg Glu Gly Glu Glu

305 310

<210> 348

<211> 181

<212> PRT

<213> Artificial sequence

<220>

<223> LEMD1

<400> 348

Met Val Asp Val Lys Cys Leu Ser Asp Cys Lys Leu Gln Asn Gln Leu

1 5 10 15

Glu Lys Leu Gly Phe Ser Pro Gly Pro Ile Leu Pro Ser Thr Arg Lys

20 25 30

Leu Tyr Glu Lys Lys Leu Val Gln Leu Leu Val Ser Pro Pro Cys Ala

35 40 45

Pro Pro Val Met Asn Gly Pro Arg Glu Leu Asp Gly Ala Gln Asp Ser

50 55 60

Asp Asp Ser Glu Glu Leu Asn Ile Ile Leu Gln Gly Asn Ile Ile Leu

65 70 75 80

Ser Thr Glu Lys Ser Lys Lys Leu Lys Lys Trp Pro Glu Ala Ser Thr

85 90 95

Thr Lys Arg Lys Ala Val Asp Thr Tyr Cys Leu Asp Tyr Lys Pro Ser

100 105 110

Lys Gly Arg Arg Trp Ala Ala Arg Ala Pro Ser Thr Arg Ile Thr Tyr

115 120 125

Gly Thr Ile Thr Lys Glu Arg Asp Tyr Cys Ala Glu Asp Gln Thr Ile

130 135 140

Glu Ser Trp Arg Glu Glu Gly Phe Pro Val Gly Leu Lys Leu Ala Val

145 150 155 160

Leu Gly Ile Phe Ile Ile Val Val Phe Val Tyr Leu Thr Val Glu Asn

165 170 175

Lys Ser Leu Phe Gly

180

<210> 349

<211> 973

<212> PRT

<213> Artificial sequence

<220>

<223> PIWIL-2

<400> 349

Met Asp Pro Phe Arg Pro Ser Phe Arg Gly Gln Ser Pro Ile His Pro

1 5 10 15

Ser Gln Cys Gln Ala Val Arg Met Pro Gly Cys Trp Pro Gln Ala Ser

20 25 30

Lys Pro Leu Asp Pro Ala Leu Gly Arg Gly Ala Pro Ala Gly Arg Gly

35 40 45

His Val Phe Gly Lys Pro Glu Glu Pro Ser Thr Gln Arg Gly Pro Ala

50 55 60

Gln Arg Glu Ser Val Gly Leu Val Ser Met Phe Arg Gly Leu Gly Ile

65 70 75 80

Glu Thr Val Ser Lys Thr Pro Leu Lys Arg Glu Met Leu Pro Ser Gly

85 90 95

Arg Gly Ile Leu Gly Arg Gly Leu Ser Ala Asn Leu Val Arg Lys Asp

100 105 110

Arg Glu Glu Leu Ser Pro Thr Phe Trp Asp Pro Lys Val Leu Ala Ala

115 120 125

Gly Asp Ser Lys Met Ala Glu Thr Ser Val Gly Trp Ser Arg Thr Leu

130 135 140

Gly Arg Gly Ser Ser Asp Ala Ser Leu Leu Pro Leu Gly Arg Ala Ala

145 150 155 160

Gly Gly Ile Ser Arg Glu Val Asp Lys Pro Pro Cys Thr Phe Ser Thr

165 170 175

Pro Ser Arg Gly Pro Pro Gln Leu Ser Ser Pro Pro Ala Leu Pro Gln

180 185 190

Ser Pro Leu His Ser Pro Asp Arg Pro Leu Val Leu Thr Val Glu His

195 200 205

Lys Glu Lys Glu Leu Ile Val Lys Gln Gly Ser Lys Gly Thr Pro Gln

210 215 220

Ser Leu Gly Leu Asn Leu Val Lys Ile Gln Cys His Asn Glu Ala Val

225 230 235 240

Tyr Gln Tyr His Val Thr Phe Ser Pro Asn Val Glu Cys Lys Ser Met

245 250 255

Arg Phe Gly Met Leu Lys Asp His Gln Ala Val Thr Gly Asn Val Thr

260 265 270

Ala Phe Asp Gly Ser Ile Leu Tyr Leu Pro Val Lys Leu Gln Gln Val

275 280 285

Leu Glu Leu Lys Ser Gln Arg Lys Thr Asp Ser Ala Glu Ile Ser Ile

290 295 300

Lys Ile Gln Met Thr Lys Ile Leu Glu Pro Cys Ser Asp Leu Cys Ile

305 310 315 320

Pro Phe Tyr Asn Val Val Phe Arg Arg Val Met Lys Leu Leu Asp Met

325 330 335

Lys Leu Val Gly Arg Asn Phe Tyr Asp Pro Thr Ser Ala Met Val Leu

340 345 350

Gln Gln His Arg Leu Gln Ile Trp Pro Gly Tyr Ala Ala Ser Ile Arg

355 360 365

Arg Thr Asp Gly Gly Leu Phe Leu Leu Ala Asp Val Ser His Lys Val

370 375 380

Ile Arg Asn Asp Cys Val Leu Asp Val Met His Ala Ile Tyr Gln Gln

385 390 395 400

Asn Lys Glu His Phe Gln Asp Glu Cys Thr Lys Leu Leu Val Gly Asn

405 410 415

Ile Val Ile Thr Arg Tyr Asn Asn Arg Thr Tyr Arg Ile Asp Asp Val

420 425 430

Asp Trp Asn Lys Thr Pro Lys Asp Ser Phe Thr Met Ser Asp Gly Lys

435 440 445

Glu Ile Thr Phe Leu Glu Tyr Tyr Ser Lys Asn Tyr Gly Ile Thr Val

450 455 460

Lys Glu Glu Asp Gln Pro Leu Leu Ile His Arg Pro Ser Glu Arg Gln

465 470 475 480

Asp Asn His Gly Met Leu Leu Lys Gly Glu Ile Leu Leu Leu Pro Glu

485 490 495

Leu Ser Phe Met Thr Gly Ile Pro Glu Lys Met Lys Lys Asp Phe Arg

500 505 510

Ala Met Lys Asp Leu Ala Gln Gln Ile Asn Leu Ser Pro Lys Gln His

515 520 525

His Ser Ala Leu Glu Cys Leu Leu Gln Arg Ile Ala Lys Asn Glu Ala

530 535 540

Ala Thr Asn Glu Leu Met Arg Trp Gly Leu Arg Leu Gln Lys Asp Val

545 550 555 560

His Lys Ile Glu Gly Arg Val Leu Pro Met Glu Arg Ile Asn Leu Lys

565 570 575

Asn Thr Ser Phe Ile Thr Ser Gln Glu Leu Asn Trp Val Lys Glu Val

580 585 590

Thr Arg Asp Pro Ser Ile Leu Thr Ile Pro Met His Phe Trp Ala Leu

595 600 605

Phe Tyr Pro Lys Arg Ala Met Asp Gln Ala Arg Glu Leu Val Asn Met

610 615 620

Leu Glu Lys Ile Ala Gly Pro Ile Gly Met Arg Met Ser Pro Pro Ala

625 630 635 640

Trp Val Glu Leu Lys Asp Asp Arg Ile Glu Thr Tyr Val Arg Thr Ile

645 650 655

Gln Ser Thr Leu Gly Ala Glu Gly Lys Ile Gln Met Val Val Cys Ile

660 665 670

Ile Met Gly Pro Arg Asp Asp Leu Tyr Gly Ala Ile Lys Lys Leu Cys

675 680 685

Cys Val Gln Ser Pro Val Pro Ser Gln Val Val Asn Val Arg Thr Ile

690 695 700

Gly Gln Pro Thr Arg Leu Arg Ser Val Ala Gln Lys Ile Leu Leu Gln

705 710 715 720

Ile Asn Cys Lys Leu Gly Gly Glu Leu Trp Gly Val Asp Ile Pro Leu

725 730 735

Lys Gln Leu Met Val Ile Gly Met Asp Val Tyr His Asp Pro Ser Arg

740 745 750

Gly Met Arg Ser Val Val Gly Phe Val Ala Ser Ile Asn Leu Thr Leu

755 760 765

Thr Lys Trp Tyr Ser Arg Val Val Phe Gln Met Pro His Gln Glu Ile

770 775 780

Val Asp Ser Leu Lys Leu Cys Leu Val Gly Ser Leu Lys Lys Phe Tyr

785 790 795 800

Glu Val Asn His Cys Leu Pro Glu Lys Ile Val Val Tyr Arg Asp Gly

805 810 815

Val Ser Asp Gly Gln Leu Lys Thr Val Ala Asn Tyr Glu Ile Pro Gln

820 825 830

Leu Gln Lys Cys Phe Glu Ala Phe Glu Asn Tyr Gln Pro Lys Met Val

835 840 845

Val Phe Val Val Gln Lys Lys Ile Ser Thr Asn Leu Tyr Leu Ala Ala

850 855 860

Pro Gln Asn Phe Val Thr Pro Thr Pro Gly Thr Val Val Asp His Thr

865 870 875 880

Ile Thr Ser Cys Glu Trp Val Asp Phe Tyr Leu Leu Ala His His Val

885 890 895

Arg Gln Gly Cys Gly Ile Pro Thr His Tyr Val Cys Val Leu Asn Thr

900 905 910

Ala Asn Leu Ser Pro Asp His Met Gln Arg Leu Thr Phe Lys Leu Cys

915 920 925

His Met Tyr Trp Asn Trp Pro Gly Thr Ile Arg Val Pro Ala Pro Cys

930 935 940

Lys Tyr Ala His Lys Leu Ala Phe Leu Ser Gly His Ile Leu His His

945 950 955 960

Glu Pro Ala Ile Gln Leu Cys Glu Asn Leu Phe Phe Leu

965 970

<210> 350

<211> 861

<212> PRT

<213> Artificial sequence

<220>

<223> HIWI

<400> 350

Met Thr Gly Arg Ala Arg Ala Arg Ala Arg Gly Arg Ala Arg Gly Gln

1 5 10 15

Glu Thr Ala Gln Leu Val Gly Ser Thr Ala Ser Gln Gln Pro Gly Tyr

20 25 30

Ile Gln Pro Arg Pro Gln Pro Pro Pro Ala Glu Gly Glu Leu Phe Gly

35 40 45

Arg Gly Arg Gln Arg Gly Thr Ala Gly Gly Thr Ala Lys Ser Gln Gly

50 55 60

Leu Gln Ile Ser Ala Gly Phe Gln Glu Leu Ser Leu Ala Glu Arg Gly

65 70 75 80

Gly Arg Arg Arg Asp Phe His Asp Leu Gly Val Asn Thr Arg Gln Asn

85 90 95

Leu Asp His Val Lys Glu Ser Lys Thr Gly Ser Ser Gly Ile Ile Val

100 105 110

Arg Leu Ser Thr Asn His Phe Arg Leu Thr Ser Arg Pro Gln Trp Ala

115 120 125

Leu Tyr Gln Tyr His Ile Asp Tyr Asn Pro Leu Met Glu Ala Arg Arg

130 135 140

Leu Arg Ser Ala Leu Leu Phe Gln His Glu Asp Leu Ile Gly Lys Cys

145 150 155 160

His Ala Phe Asp Gly Thr Ile Leu Phe Leu Pro Lys Arg Leu Gln Gln

165 170 175

Lys Val Thr Glu Val Phe Ser Lys Thr Arg Asn Gly Glu Asp Val Arg

180 185 190

Ile Thr Ile Thr Leu Thr Asn Glu Leu Pro Pro Thr Ser Pro Thr Cys

195 200 205

Leu Gln Phe Tyr Asn Ile Ile Phe Arg Arg Leu Leu Lys Ile Met Asn

210 215 220

Leu Gln Gln Ile Gly Arg Asn Tyr Tyr Asn Pro Asn Asp Pro Ile Asp

225 230 235 240

Ile Pro Ser His Arg Leu Val Ile Trp Pro Gly Phe Thr Thr Ser Ile

245 250 255

Leu Gln Tyr Glu Asn Ser Ile Met Leu Cys Thr Asp Val Ser His Lys

260 265 270

Val Leu Arg Ser Glu Thr Val Leu Asp Phe Met Phe Asn Phe Tyr His

275 280 285

Gln Thr Glu Glu His Lys Phe Gln Glu Gln Val Ser Lys Glu Leu Ile

290 295 300

Gly Leu Val Val Leu Thr Lys Tyr Asn Asn Lys Thr Tyr Arg Val Asp

305 310 315 320

Asp Ile Asp Trp Asp Gln Asn Pro Lys Ser Thr Phe Lys Lys Ala Asp

325 330 335

Gly Ser Glu Val Ser Phe Leu Glu Tyr Tyr Arg Lys Gln Tyr Asn Gln

340 345 350

Glu Ile Thr Asp Leu Lys Gln Pro Val Leu Val Ser Gln Pro Lys Arg

355 360 365

Arg Arg Gly Pro Gly Gly Thr Leu Pro Gly Pro Ala Met Leu Ile Pro

370 375 380

Glu Leu Cys Tyr Leu Thr Gly Leu Thr Asp Lys Met Arg Asn Asp Phe

385 390 395 400

Asn Val Met Lys Asp Leu Ala Val His Thr Arg Leu Thr Pro Glu Gln

405 410 415

Arg Gln Arg Glu Val Gly Arg Leu Ile Asp Tyr Ile His Lys Asn Asp

420 425 430

Asn Val Gln Arg Glu Leu Arg Asp Trp Gly Leu Ser Phe Asp Ser Asn

435 440 445

Leu Leu Ser Phe Ser Gly Arg Ile Leu Gln Thr Glu Lys Ile His Gln

450 455 460

Gly Gly Lys Thr Phe Asp Tyr Asn Pro Gln Phe Ala Asp Trp Ser Lys

465 470 475 480

Glu Thr Arg Gly Ala Pro Leu Ile Ser Val Lys Pro Leu Asp Asn Trp

485 490 495

Leu Leu Ile Tyr Thr Arg Arg Asn Tyr Glu Ala Ala Asn Ser Leu Ile

500 505 510

Gln Asn Leu Phe Lys Val Thr Pro Ala Met Gly Met Gln Met Arg Lys

515 520 525

Ala Ile Met Ile Glu Val Asp Asp Arg Thr Glu Ala Tyr Leu Arg Val

530 535 540

Leu Gln Gln Lys Val Thr Ala Asp Thr Gln Ile Val Val Cys Leu Leu

545 550 555 560

Ser Ser Asn Arg Lys Asp Lys Tyr Asp Ala Ile Lys Lys Tyr Leu Cys

565 570 575

Thr Asp Cys Pro Thr Pro Ser Gln Cys Val Val Ala Arg Thr Leu Gly

580 585 590

Lys Gln Gln Thr Val Met Ala Ile Ala Thr Lys Ile Ala Leu Gln Met

595 600 605

Asn Cys Lys Met Gly Gly Glu Leu Trp Arg Val Asp Ile Pro Leu Lys

610 615 620

Leu Val Met Ile Val Gly Ile Asp Cys Tyr His Asp Met Thr Ala Gly

625 630 635 640

Arg Arg Ser Ile Ala Gly Phe Val Ala Ser Ile Asn Glu Gly Met Thr

645 650 655

Arg Trp Phe Ser Arg Cys Ile Phe Gln Asp Arg Gly Gln Glu Leu Val

660 665 670

Asp Gly Leu Lys Val Cys Leu Gln Ala Ala Leu Arg Ala Trp Asn Ser

675 680 685

Cys Asn Glu Tyr Met Pro Ser Arg Ile Ile Val Tyr Arg Asp Gly Val

690 695 700

Gly Asp Gly Gln Leu Lys Thr Leu Val Asn Tyr Glu Val Pro Gln Phe

705 710 715 720

Leu Asp Cys Leu Lys Ser Ile Gly Arg Gly Tyr Asn Pro Arg Leu Thr

725 730 735

Val Ile Val Val Lys Lys Arg Val Asn Thr Arg Phe Phe Ala Gln Ser

740 745 750

Gly Gly Arg Leu Gln Asn Pro Leu Pro Gly Thr Val Ile Asp Val Glu

755 760 765

Val Thr Arg Pro Glu Trp Tyr Asp Phe Phe Ile Val Ser Gln Ala Val

770 775 780

Arg Ser Gly Ser Val Ser Pro Thr His Tyr Asn Val Ile Tyr Asp Asn

785 790 795 800

Ser Gly Leu Lys Pro Asp His Ile Gln Arg Leu Thr Tyr Lys Leu Cys

805 810 815

His Ile Tyr Tyr Asn Trp Pro Gly Val Ile Arg Val Pro Ala Pro Cys

820 825 830

Gln Tyr Ala His Lys Leu Ala Phe Leu Val Gly Gln Ser Ile His Arg

835 840 845

Glu Pro Asn Leu Ser Leu Ser Asn Arg Leu Tyr Tyr Leu

850 855 860

<210> 351

<211> 1544

<212> PRT

<213> Artificial sequence

<220>

<223> PLU-1

<400> 351

Met Glu Ala Ala Thr Thr Leu His Pro Gly Pro Arg Pro Ala Leu Pro

1 5 10 15

Leu Gly Gly Pro Gly Pro Leu Gly Glu Phe Leu Pro Pro Pro Glu Cys

20 25 30

Pro Val Phe Glu Pro Ser Trp Glu Glu Phe Ala Asp Pro Phe Ala Phe

35 40 45

Ile His Lys Ile Arg Pro Ile Ala Glu Gln Thr Gly Ile Cys Lys Val

50 55 60

Arg Pro Pro Pro Asp Trp Gln Pro Pro Phe Ala Cys Asp Val Asp Lys

65 70 75 80

Leu His Phe Thr Pro Arg Ile Gln Arg Leu Asn Glu Leu Glu Ala Gln

85 90 95

Thr Arg Val Lys Leu Asn Phe Leu Asp Gln Ile Ala Lys Tyr Trp Glu

100 105 110

Leu Gln Gly Ser Thr Leu Lys Ile Pro His Val Glu Arg Lys Ile Leu

115 120 125

Asp Leu Phe Gln Leu Asn Lys Leu Val Ala Glu Glu Gly Gly Phe Ala

130 135 140

Val Val Cys Lys Asp Arg Lys Trp Thr Lys Ile Ala Thr Lys Met Gly

145 150 155 160

Phe Ala Pro Gly Lys Ala Val Gly Ser His Ile Arg Gly His Tyr Glu

165 170 175

Arg Ile Leu Asn Pro Tyr Asn Leu Phe Leu Ser Gly Asp Ser Leu Arg

180 185 190

Cys Leu Gln Lys Pro Asn Leu Thr Thr Asp Thr Lys Asp Lys Glu Tyr

195 200 205

Lys Pro His Asp Ile Pro Gln Arg Gln Ser Val Gln Pro Ser Glu Thr

210 215 220

Cys Pro Pro Ala Arg Arg Ala Lys Arg Met Arg Ala Glu Ala Met Asn

225 230 235 240

Ile Lys Ile Glu Pro Glu Glu Thr Thr Glu Ala Arg Thr His Asn Leu

245 250 255

Arg Arg Arg Met Gly Cys Pro Thr Pro Lys Cys Glu Asn Glu Lys Glu

260 265 270

Met Lys Ser Ser Ile Lys Gln Glu Pro Ile Glu Arg Lys Asp Tyr Ile

275 280 285

Val Glu Asn Glu Lys Glu Lys Pro Lys Ser Arg Ser Lys Lys Ala Thr

290 295 300

Asn Ala Val Asp Leu Tyr Val Cys Leu Leu Cys Gly Ser Gly Asn Asp

305 310 315 320

Glu Asp Arg Leu Leu Leu Cys Asp Gly Cys Asp Asp Ser Tyr His Thr

325 330 335

Phe Cys Leu Ile Pro Pro Leu His Asp Val Pro Lys Gly Asp Trp Arg

340 345 350

Cys Pro Lys Cys Leu Ala Gln Glu Cys Ser Lys Pro Gln Glu Ala Phe

355 360 365

Gly Phe Glu Gln Ala Ala Arg Asp Tyr Thr Leu Arg Thr Phe Gly Glu

370 375 380

Met Ala Asp Ala Phe Lys Ser Asp Tyr Phe Asn Met Pro Val His Met

385 390 395 400

Val Pro Thr Glu Leu Val Glu Lys Glu Phe Trp Arg Leu Val Ser Thr

405 410 415

Ile Glu Glu Asp Val Thr Val Glu Tyr Gly Ala Asp Ile Ala Ser Lys

420 425 430

Glu Phe Gly Ser Gly Phe Pro Val Arg Asp Gly Lys Ile Lys Leu Ser

435 440 445

Pro Glu Glu Glu Glu Tyr Leu Asp Ser Gly Trp Asn Leu Asn Asn Met

450 455 460

Pro Val Met Glu Gln Ser Val Leu Ala His Ile Thr Ala Asp Ile Cys

465 470 475 480

Gly Met Lys Leu Pro Trp Leu Tyr Val Gly Met Cys Phe Ser Ser Phe

485 490 495

Cys Trp His Ile Glu Asp His Trp Ser Tyr Ser Ile Asn Tyr Leu His

500 505 510

Trp Gly Glu Pro Lys Thr Trp Tyr Gly Val Pro Gly Tyr Ala Ala Glu

515 520 525

Gln Leu Glu Asn Val Met Lys Lys Leu Ala Pro Glu Leu Phe Val Ser

530 535 540

Gln Pro Asp Leu Leu His Gln Leu Val Thr Ile Met Asn Pro Asn Thr

545 550 555 560

Leu Met Thr His Glu Val Pro Val Tyr Arg Thr Asn Gln Cys Ala Gly

565 570 575

Glu Phe Val Ile Thr Phe Pro Arg Ala Tyr His Ser Gly Phe Asn Gln

580 585 590

Gly Phe Asn Phe Ala Glu Ala Val Asn Phe Cys Thr Val Asp Trp Leu

595 600 605

Pro Leu Gly Arg Gln Cys Val Glu His Tyr Arg Leu Leu His Arg Tyr

610 615 620

Cys Val Phe Ser His Asp Glu Met Ile Cys Lys Met Ala Ser Lys Ala

625 630 635 640

Asp Val Leu Asp Val Val Val Ala Ser Thr Val Gln Lys Asp Met Ala

645 650 655

Ile Met Ile Glu Asp Glu Lys Ala Leu Arg Glu Thr Val Arg Lys Leu

660 665 670

Gly Val Ile Asp Ser Glu Arg Met Asp Phe Glu Leu Leu Pro Asp Asp

675 680 685

Glu Arg Gln Cys Val Lys Cys Lys Thr Thr Cys Phe Met Ser Ala Ile

690 695 700

Ser Cys Ser Cys Lys Pro Gly Leu Leu Val Cys Leu His His Val Lys

705 710 715 720

Glu Leu Cys Ser Cys Pro Pro Tyr Lys Tyr Lys Leu Arg Tyr Arg Tyr

725 730 735

Thr Leu Asp Asp Leu Tyr Pro Met Met Asn Ala Leu Lys Leu Arg Ala

740 745 750

Glu Ser Tyr Asn Glu Trp Ala Leu Asn Val Asn Glu Ala Leu Glu Ala

755 760 765

Lys Ile Asn Lys Lys Lys Ser Leu Val Ser Phe Lys Ala Leu Ile Glu

770 775 780

Glu Ser Glu Met Lys Lys Phe Pro Asp Asn Asp Leu Leu Arg His Leu

785 790 795 800

Arg Leu Val Thr Gln Asp Ala Glu Lys Cys Ala Ser Val Ala Gln Gln

805 810 815

Leu Leu Asn Gly Lys Arg Gln Thr Arg Tyr Arg Ser Gly Gly Gly Lys

820 825 830

Ser Gln Asn Gln Leu Thr Val Asn Glu Leu Arg Gln Phe Val Thr Gln

835 840 845

Leu Tyr Ala Leu Pro Cys Val Leu Ser Gln Thr Pro Leu Leu Lys Asp

850 855 860

Leu Leu Asn Arg Val Glu Asp Phe Gln Gln His Ser Gln Lys Leu Leu

865 870 875 880

Ser Glu Glu Thr Pro Ser Ala Ala Glu Leu Gln Asp Leu Leu Asp Val

885 890 895

Ser Phe Glu Phe Asp Val Glu Leu Pro Gln Leu Ala Glu Met Arg Ile

900 905 910

Arg Leu Glu Gln Ala Arg Trp Leu Glu Glu Val Gln Gln Ala Cys Leu

915 920 925

Asp Pro Ser Ser Leu Thr Leu Asp Asp Met Arg Arg Leu Ile Asp Leu

930 935 940

Gly Val Gly Leu Ala Pro Tyr Ser Ala Val Glu Lys Ala Met Ala Arg

945 950 955 960

Leu Gln Glu Leu Leu Thr Val Ser Glu His Trp Asp Asp Lys Ala Lys

965 970 975

Ser Leu Leu Lys Ala Arg Pro Arg His Ser Leu Asn Ser Leu Ala Thr

980 985 990

Ala Val Lys Glu Ile Glu Glu Ile Pro Ala Tyr Leu Pro Asn Gly Ala

995 1000 1005

Ala Leu Lys Asp Ser Val Gln Arg Ala Arg Asp Trp Leu Gln Asp

1010 1015 1020

Val Glu Gly Leu Gln Ala Gly Gly Arg Val Pro Val Leu Asp Thr

1025 1030 1035

Leu Ile Glu Leu Val Thr Arg Gly Arg Ser Ile Pro Val His Leu

1040 1045 1050

Asn Ser Leu Pro Arg Leu Glu Thr Leu Val Ala Glu Val Gln Ala

1055 1060 1065

Trp Lys Glu Cys Ala Val Asn Thr Phe Leu Thr Glu Asn Ser Pro

1070 1075 1080

Tyr Ser Leu Leu Glu Val Leu Cys Pro Arg Cys Asp Ile Gly Leu

1085 1090 1095

Leu Gly Leu Lys Arg Lys Gln Arg Lys Leu Lys Glu Pro Leu Pro

1100 1105 1110

Asn Gly Lys Lys Lys Ser Thr Lys Leu Glu Ser Leu Ser Asp Leu

1115 1120 1125

Glu Arg Ala Leu Thr Glu Ser Lys Glu Thr Ala Ser Ala Met Ala

1130 1135 1140

Thr Leu Gly Glu Ala Arg Leu Arg Glu Met Glu Ala Leu Gln Ser

1145 1150 1155

Leu Arg Leu Ala Asn Glu Gly Lys Leu Leu Ser Pro Leu Gln Asp

1160 1165 1170

Val Asp Ile Lys Ile Cys Leu Cys Gln Lys Ala Pro Ala Ala Pro

1175 1180 1185

Met Ile Gln Cys Glu Leu Cys Arg Asp Ala Phe His Thr Ser Cys

1190 1195 1200

Val Ala Val Pro Ser Ile Ser Gln Gly Leu Arg Ile Trp Leu Cys

1205 1210 1215

Pro His Cys Arg Arg Ser Glu Lys Pro Pro Leu Glu Lys Ile Leu

1220 1225 1230

Pro Leu Leu Ala Ser Leu Gln Arg Ile Arg Val Arg Leu Pro Glu

1235 1240 1245

Gly Asp Ala Leu Arg Tyr Met Ile Glu Arg Thr Val Asn Trp Gln

1250 1255 1260

His Arg Ala Gln Gln Leu Leu Ser Ser Gly Asn Leu Lys Phe Val

1265 1270 1275

Gln Asp Arg Val Gly Ser Gly Leu Leu Tyr Ser Arg Trp Gln Ala

1280 1285 1290

Ser Ala Gly Gln Val Ser Asp Thr Asn Lys Val Ser Gln Pro Pro

1295 1300 1305

Gly Thr Thr Ser Phe Ser Leu Pro Asp Asp Trp Asp Asn Arg Thr

1310 1315 1320

Ser Tyr Leu His Ser Pro Phe Ser Thr Gly Arg Ser Cys Ile Pro

1325 1330 1335

Leu His Gly Val Ser Pro Glu Val Asn Glu Leu Leu Met Glu Ala

1340 1345 1350

Gln Leu Leu Gln Val Ser Leu Pro Glu Ile Gln Glu Leu Tyr Gln

1355 1360 1365

Thr Leu Leu Ala Lys Pro Ser Pro Ala Gln Gln Thr Asp Arg Ser

1370 1375 1380

Ser Pro Val Arg Pro Ser Ser Glu Lys Asn Asp Cys Cys Arg Gly

1385 1390 1395

Lys Arg Asp Gly Ile Asn Ser Leu Glu Arg Lys Leu Lys Arg Arg

1400 1405 1410

Leu Glu Arg Glu Gly Leu Ser Ser Glu Arg Trp Glu Arg Val Lys

1415 1420 1425

Lys Met Arg Thr Pro Lys Lys Lys Lys Ile Lys Leu Ser His Pro

1430 1435 1440

Lys Asp Met Asn Asn Phe Lys Leu Glu Arg Glu Arg Ser Tyr Glu

1445 1450 1455

Leu Val Arg Ser Ala Glu Thr His Ser Leu Pro Ser Asp Thr Ser

1460 1465 1470

Tyr Ser Glu Gln Glu Asp Ser Glu Asp Glu Asp Ala Ile Cys Pro

1475 1480 1485

Ala Val Ser Cys Leu Gln Pro Glu Gly Asp Glu Val Asp Trp Val

1490 1495 1500

Gln Cys Asp Gly Ser Cys Asn Gln Trp Phe His Gln Val Cys Val

1505 1510 1515

Gly Val Ser Pro Glu Met Ala Glu Lys Glu Asp Tyr Ile Cys Val

1520 1525 1530

Arg Cys Thr Val Lys Asp Ala Pro Ser Arg Lys

1535 1540

<210> 352

<211> 698

<212> PRT

<213> Artificial sequence

<220>

<223> TSGA10

<400> 352

Met Met Arg Ser Arg Ser Lys Ser Pro Arg Arg Pro Ser Pro Thr Ala

1 5 10 15

Arg Gly Ala Asn Cys Asp Val Glu Leu Leu Lys Thr Thr Thr Arg Asp

20 25 30

Arg Glu Glu Leu Lys Cys Met Leu Glu Lys Tyr Glu Arg His Leu Ala

35 40 45

Glu Ile Gln Gly Asn Val Lys Val Leu Lys Ser Glu Arg Asp Lys Ile

50 55 60

Phe Leu Leu Tyr Glu Gln Ala Gln Glu Glu Ile Thr Arg Leu Arg Arg

65 70 75 80

Glu Met Met Lys Ser Cys Lys Ser Pro Lys Ser Thr Thr Ala His Ala

85 90 95

Ile Leu Arg Arg Val Glu Thr Glu Arg Asp Val Ala Phe Thr Asp Leu

100 105 110

Arg Arg Met Thr Thr Glu Arg Asp Ser Leu Arg Glu Arg Leu Lys Ile

115 120 125

Ala Gln Glu Thr Ala Phe Asn Glu Lys Ala His Leu Glu Gln Arg Ile

130 135 140

Glu Glu Leu Glu Cys Thr Val His Asn Leu Asp Asp Glu Arg Met Glu

145 150 155 160

Gln Met Ser Asn Met Thr Leu Met Lys Glu Thr Ile Ser Thr Val Glu

165 170 175

Lys Glu Met Lys Ser Leu Ala Arg Lys Ala Met Asp Thr Glu Ser Glu

180 185 190

Leu Gly Arg Gln Lys Ala Glu Asn Asn Ser Leu Arg Leu Leu Tyr Glu

195 200 205

Asn Thr Glu Lys Asp Leu Ser Asp Thr Gln Arg His Leu Ala Lys Lys

210 215 220

Lys Tyr Glu Leu Gln Leu Thr Gln Glu Lys Ile Met Cys Leu Asp Glu

225 230 235 240

Lys Ile Asp Asn Phe Thr Arg Gln Asn Ile Ala Gln Arg Glu Glu Ile

245 250 255

Ser Ile Leu Gly Gly Thr Leu Asn Asp Leu Ala Lys Glu Lys Glu Cys

260 265 270

Leu Gln Ala Cys Leu Asp Lys Lys Ser Glu Asn Ile Ala Ser Leu Gly

275 280 285

Glu Ser Leu Ala Met Lys Glu Lys Thr Ile Ser Gly Met Lys Asn Ile

290 295 300

Ile Ala Glu Met Glu Gln Ala Ser Arg Gln Cys Thr Glu Ala Leu Ile

305 310 315 320

Val Cys Glu Gln Asp Val Ser Arg Met Arg Arg Gln Leu Asp Glu Thr

325 330 335

Asn Asp Glu Leu Ala Gln Ile Ala Arg Glu Arg Asp Ile Leu Ala His

340 345 350

Asp Asn Asp Asn Leu Gln Glu Gln Phe Ala Lys Ala Lys Gln Glu Asn

355 360 365

Gln Ala Leu Ser Lys Lys Leu Asn Asp Thr His Asn Glu Leu Asn Asp

370 375 380

Ile Lys Gln Lys Val Gln Asp Thr Asn Leu Glu Val Asn Lys Leu Lys

385 390 395 400

Asn Ile Leu Lys Ser Glu Glu Ser Glu Asn Arg Gln Met Met Glu Gln

405 410 415

Leu Arg Lys Ala Asn Glu Asp Ala Glu Asn Trp Glu Asn Lys Ala Arg

420 425 430

Gln Ser Glu Ala Asp Asn Asn Thr Leu Lys Leu Glu Leu Ile Thr Ala

435 440 445

Glu Ala Glu Gly Asn Arg Leu Lys Glu Lys Val Asp Ser Leu Asn Arg

450 455 460

Glu Val Glu Gln His Leu Asn Ala Glu Arg Ser Tyr Lys Ser Gln Ile

465 470 475 480

Ser Thr Leu His Lys Ser Val Val Lys Met Glu Glu Glu Leu Gln Lys

485 490 495

Val Gln Phe Glu Lys Val Ser Ala Leu Ala Asp Leu Ser Ser Thr Arg

500 505 510

Glu Leu Cys Ile Lys Leu Asp Ser Ser Lys Glu Leu Leu Asn Arg Gln

515 520 525

Leu Val Ala Lys Asp Gln Glu Ile Glu Met Arg Glu Asn Glu Leu Asp

530 535 540

Ser Ala His Ser Glu Ile Glu Leu Leu Arg Ser Gln Met Ala Asn Glu

545 550 555 560

Arg Ile Ser Met Gln Asn Leu Glu Ala Leu Leu Val Ala Asn Arg Asp

565 570 575

Lys Glu Tyr Gln Ser Gln Ile Ala Leu Gln Glu Lys Glu Ser Glu Ile

580 585 590

Gln Leu Leu Lys Glu His Leu Cys Leu Ala Glu Asn Lys Met Ala Ile

595 600 605

Gln Ser Arg Asp Val Ala Gln Phe Arg Asn Val Val Thr Gln Leu Glu

610 615 620

Ala Asp Leu Asp Ile Thr Lys Arg Gln Leu Gly Thr Glu Arg Phe Glu

625 630 635 640

Arg Glu Arg Ala Val Gln Glu Leu Arg Arg Gln Asn Tyr Ser Ser Asn

645 650 655

Ala Tyr His Met Ser Ser Thr Met Lys Pro Asn Thr Lys Cys His Ser

660 665 670

Pro Glu Arg Ala His His Arg Ser Pro Asp Arg Gly Leu Asp Arg Ser

675 680 685

Leu Glu Glu Asn Leu Cys Tyr Arg Asp Phe

690 695

<210> 353

<211> 257

<212> PRT

<213> Artificial sequence

<220>

<223> ODF-4

<400> 353

Met Asp Ala Glu Tyr Ser Gly Asn Glu Phe Pro Arg Ser Glu Gly Glu

1 5 10 15

Arg Asp Gln His Gln Arg Pro Gly Lys Glu Arg Lys Ser Gly Glu Ala

20 25 30

Gly Trp Gly Thr Gly Glu Leu Gly Gln Asp Gly Arg Leu Leu Ser Ser

35 40 45

Thr Leu Ser Leu Ser Ser Asn Arg Ser Leu Gly Gln Arg Gln Asn Ser

50 55 60

Pro Leu Pro Phe Gln Trp Arg Ile Thr His Ser Phe Arg Trp Met Ala

65 70 75 80

Gln Val Leu Ala Ser Glu Leu Ser Leu Val Ala Phe Ile Leu Leu Leu

85 90 95

Val Val Ala Phe Ser Lys Lys Trp Leu Asp Leu Ser Arg Ser Leu Phe

100 105 110

Tyr Gln Arg Trp Pro Val Asp Val Ser Asn Arg Ile His Thr Ser Ala

115 120 125

His Val Met Ser Met Gly Leu Leu His Phe Tyr Lys Ser Arg Ser Cys

130 135 140

Ser Asp Leu Glu Asn Gly Lys Val Thr Phe Ile Phe Ser Thr Leu Met

145 150 155 160

Leu Phe Pro Ile Asn Ile Trp Ile Phe Glu Leu Glu Arg Asn Val Ser

165 170 175

Ile Pro Ile Gly Trp Ser Tyr Phe Ile Gly Trp Leu Val Leu Ile Leu

180 185 190

Tyr Phe Thr Cys Ala Ile Leu Cys Tyr Phe Asn His Lys Ser Phe Trp

195 200 205

Ser Leu Ile Leu Ser His Pro Ser Gly Ala Val Ser Cys Ser Ser Ser

210 215 220

Phe Gly Ser Val Glu Glu Ser Pro Arg Ala Gln Thr Ile Thr Asp Thr

225 230 235 240

Pro Ile Thr Gln Glu Gly Val Leu Asp Pro Glu Gln Lys Asp Thr His

245 250 255

Val

<210> 354

<211> 151

<212> PRT

<213> Artificial sequence

<220>

<223> SP17

<400> 354

Met Ser Ile Pro Phe Ser Asn Thr His Tyr Arg Ile Pro Gln Gly Phe

1 5 10 15

Gly Asn Leu Leu Glu Gly Leu Thr Arg Glu Ile Leu Arg Glu Gln Pro

20 25 30

Asp Asn Ile Pro Ala Phe Ala Ala Ala Tyr Phe Glu Ser Leu Leu Glu

35 40 45

Lys Arg Glu Lys Thr Asn Phe Asp Pro Ala Glu Trp Gly Ser Lys Val

50 55 60

Glu Asp Arg Phe Tyr Asn Asn His Ala Phe Glu Glu Gln Glu Pro Pro

65 70 75 80

Glu Lys Ser Asp Pro Lys Gln Glu Glu Ser Gln Ile Ser Gly Lys Glu

85 90 95

Glu Glu Thr Ser Val Thr Ile Leu Asp Ser Ser Glu Glu Asp Lys Glu

100 105 110

Lys Glu Glu Val Ala Ala Val Lys Ile Gln Ala Ala Phe Arg Gly His

115 120 125

Ile Ala Arg Glu Glu Ala Lys Lys Met Lys Thr Asn Ser Leu Gln Asn

130 135 140

Glu Glu Lys Glu Glu Asn Lys

145 150

<210> 355

<211> 1116

<212> PRT

<213> Artificial sequence

<220>

<223> RHOXF-2

<400> 355

Met Ala Ala Asp Leu Asn Leu Glu Trp Ile Ser Leu Pro Arg Ser Trp

1 5 10 15

Thr Tyr Gly Ile Thr Arg Gly Gly Arg Val Phe Phe Ile Asn Glu Glu

20 25 30

Ala Lys Ser Thr Thr Trp Leu His Pro Val Thr Gly Glu Ala Val Val

35 40 45

Thr Gly His Arg Arg Gln Ser Thr Asp Leu Pro Thr Gly Trp Glu Glu

50 55 60

Ala Tyr Thr Phe Glu Gly Ala Arg Tyr Tyr Ile Asn His Asn Glu Arg

65 70 75 80

Lys Val Thr Cys Lys His Pro Val Thr Gly Gln Pro Ser Gln Asp Asn

85 90 95

Cys Ile Phe Val Val Asn Glu Gln Thr Val Ala Thr Met Thr Ser Glu

100 105 110

Glu Lys Lys Glu Arg Pro Ile Ser Met Ile Asn Glu Ala Ser Asn Tyr

115 120 125

Asn Val Thr Ser Asp Tyr Ala Val His Pro Met Ser Pro Val Gly Arg

130 135 140

Thr Ser Arg Ala Ser Lys Lys Val His Asn Phe Gly Lys Arg Ser Asn

145 150 155 160

Ser Ile Lys Arg Asn Pro Asn Ala Pro Val Val Arg Arg Gly Trp Leu

165 170 175

Tyr Lys Gln Asp Ser Thr Gly Met Lys Leu Trp Lys Lys Arg Trp Phe

180 185 190

Val Leu Ser Asp Leu Cys Leu Phe Tyr Tyr Arg Asp Glu Lys Glu Glu

195 200 205

Gly Ile Leu Gly Ser Ile Leu Leu Pro Ser Phe Gln Ile Ala Leu Leu

210 215 220

Thr Ser Glu Asp His Ile Asn Arg Lys Tyr Ala Phe Lys Ala Ala His

225 230 235 240

Pro Asn Met Arg Thr Tyr Tyr Phe Cys Thr Asp Thr Gly Lys Glu Met

245 250 255

Glu Leu Trp Met Lys Ala Met Leu Asp Ala Ala Leu Val Gln Thr Glu

260 265 270

Pro Val Lys Arg Val Asp Lys Ile Thr Ser Glu Asn Ala Pro Thr Lys

275 280 285

Glu Thr Asn Asn Ile Pro Asn His Arg Val Leu Ile Lys Pro Glu Ile

290 295 300

Gln Asn Asn Gln Lys Asn Lys Glu Met Ser Lys Ile Glu Glu Lys Lys

305 310 315 320

Ala Leu Glu Ala Glu Lys Tyr Gly Phe Gln Lys Asp Gly Gln Asp Arg

325 330 335

Pro Leu Thr Lys Ile Asn Ser Val Lys Leu Asn Ser Leu Pro Ser Glu

340 345 350

Tyr Glu Ser Gly Ser Ala Cys Pro Ala Gln Thr Val His Tyr Arg Pro

355 360 365

Ile Asn Leu Ser Ser Ser Glu Asn Lys Ile Val Asn Val Ser Leu Ala

370 375 380

Asp Leu Arg Gly Gly Asn Arg Pro Asn Thr Gly Pro Leu Tyr Thr Glu

385 390 395 400

Ala Asp Arg Val Ile Gln Arg Thr Asn Ser Met Gln Gln Leu Glu Gln

405 410 415

Trp Ile Lys Ile Gln Lys Gly Arg Gly His Glu Glu Glu Thr Arg Gly

420 425 430

Val Ile Ser Tyr Gln Thr Leu Pro Arg Asn Met Pro Ser His Arg Ala

435 440 445

Gln Ile Met Ala Arg Tyr Pro Glu Gly Tyr Arg Thr Leu Pro Arg Asn

450 455 460

Ser Lys Thr Arg Pro Glu Ser Ile Cys Ser Val Thr Pro Ser Thr His

465 470 475 480

Asp Lys Thr Leu Gly Pro Gly Ala Glu Glu Lys Arg Arg Ser Met Arg

485 490 495

Asp Asp Thr Met Trp Gln Leu Tyr Glu Trp Gln Gln Arg Gln Phe Tyr

500 505 510

Asn Lys Gln Ser Thr Leu Pro Arg His Ser Thr Leu Ser Ser Pro Lys

515 520 525

Thr Met Val Asn Ile Ser Asp Gln Thr Met His Ser Ile Pro Thr Ser

530 535 540

Pro Ser His Gly Ser Ile Ala Ala Tyr Gln Gly Tyr Ser Pro Gln Arg

545 550 555 560

Thr Tyr Arg Ser Glu Val Ser Ser Pro Ile Gln Arg Gly Asp Val Thr

565 570 575

Ile Asp Arg Arg His Arg Ala His His Pro Lys His Val Tyr Val Pro

580 585 590

Asp Arg Arg Ser Val Pro Ala Gly Leu Thr Leu Gln Ser Val Ser Pro

595 600 605

Gln Ser Leu Gln Gly Lys Thr Leu Ser Gln Asp Glu Gly Arg Gly Thr

610 615 620

Leu Tyr Lys Tyr Arg Pro Glu Glu Val Asp Ile Asp Ala Lys Leu Ser

625 630 635 640

Arg Leu Cys Glu Gln Asp Lys Val Val His Ala Leu Glu Glu Lys Leu

645 650 655

Gln Gln Leu His Lys Glu Lys Tyr Thr Leu Glu Gln Ala Leu Leu Ser

660 665 670

Ala Ser Gln Glu Ile Glu Met His Ala Asp Asn Pro Ala Ala Ile Gln

675 680 685

Thr Val Val Leu Gln Arg Asp Asp Leu Gln Asn Gly Leu Leu Ser Thr

690 695 700

Cys Arg Glu Leu Ser Arg Ala Thr Ala Glu Leu Glu Arg Ala Trp Arg

705 710 715 720

Glu Tyr Asp Lys Leu Glu Tyr Asp Val Thr Val Thr Arg Asn Gln Met

725 730 735

Gln Glu Gln Leu Asp His Leu Gly Glu Val Gln Thr Glu Ser Ala Gly

740 745 750

Ile Gln Arg Ala Gln Ile Gln Lys Glu Leu Trp Arg Ile Gln Asp Val

755 760 765

Met Glu Gly Leu Ser Lys His Lys Gln Gln Arg Gly Thr Thr Glu Ile

770 775 780

Gly Met Ile Gly Ser Lys Pro Phe Ser Thr Val Lys Tyr Lys Asn Glu

785 790 795 800

Gly Pro Asp Tyr Arg Leu Tyr Lys Ser Glu Pro Glu Leu Thr Thr Val

805 810 815

Ala Glu Val Asp Glu Ser Asn Gly Glu Glu Lys Ser Glu Pro Val Ser

820 825 830

Glu Ile Glu Thr Ser Val Val Lys Gly Ser His Phe Pro Val Gly Val

835 840 845

Val Pro Pro Arg Ala Lys Ser Pro Thr Pro Glu Ser Ser Thr Ile Ala

850 855 860

Ser Tyr Val Thr Leu Arg Lys Thr Lys Lys Met Met Asp Leu Arg Thr

865 870 875 880

Glu Arg Pro Arg Ser Ala Val Glu Gln Leu Cys Leu Ala Glu Ser Thr

885 890 895

Arg Pro Arg Met Thr Val Glu Glu Gln Met Glu Arg Ile Arg Arg His

900 905 910

Gln Gln Ala Cys Leu Arg Glu Lys Lys Lys Gly Leu Asn Val Ile Gly

915 920 925

Ala Ser Asp Gln Ser Pro Leu Gln Ser Pro Ser Asn Leu Arg Asp Asn

930 935 940

Pro Phe Arg Thr Thr Gln Thr Arg Arg Arg Asp Asp Lys Glu Leu Asp

945 950 955 960

Thr Ala Ile Arg Glu Asn Asp Val Lys Pro Asp His Glu Thr Pro Ala

965 970 975

Thr Glu Ile Val Gln Leu Lys Glu Thr Glu Pro Gln Asn Val Asp Phe

980 985 990

Ser Lys Glu Leu Lys Lys Thr Glu Asn Ile Ser Tyr Glu Met Leu Phe

995 1000 1005

Glu Pro Glu Pro Asn Gly Val Asn Ser Val Glu Met Met Asp Lys

1010 1015 1020

Glu Arg Asn Lys Asp Lys Met Pro Glu Asp Val Thr Phe Ser Pro

1025 1030 1035

Gln Asp Glu Thr Gln Thr Ala Asn His Lys Pro Glu Glu His Pro

1040 1045 1050

Glu Glu Asn Thr Lys Asn Ser Val Asp Glu Gln Glu Glu Thr Val

1055 1060 1065

Ile Ser Tyr Glu Ser Thr Pro Glu Val Ser Arg Gly Asn Gln Thr

1070 1075 1080

Met Ala Val Lys Ser Leu Ser Pro Ser Pro Glu Ser Ser Ala Ser

1085 1090 1095

Pro Val Pro Ser Thr Gln Pro Gln Leu Thr Glu Gly Ser His Phe

1100 1105 1110

Met Cys Val

1115

<210> 356

<211> 180

<212> PRT

<213> Artificial sequence

<220>

<223> NY-ESO-1

<400> 356

Met Gln Ala Glu Gly Arg Gly Thr Gly Gly Ser Thr Gly Asp Ala Asp

1 5 10 15

Gly Pro Gly Gly Pro Gly Ile Pro Asp Gly Pro Gly Gly Asn Ala Gly

20 25 30

Gly Pro Gly Glu Ala Gly Ala Thr Gly Gly Arg Gly Pro Arg Gly Ala

35 40 45

Gly Ala Ala Arg Ala Ser Gly Pro Gly Gly Gly Ala Pro Arg Gly Pro

50 55 60

His Gly Gly Ala Ala Ser Gly Leu Asn Gly Cys Cys Arg Cys Gly Ala

65 70 75 80

Arg Gly Pro Glu Ser Arg Leu Leu Glu Phe Tyr Leu Ala Met Pro Phe

85 90 95

Ala Thr Pro Met Glu Ala Glu Leu Ala Arg Arg Ser Leu Ala Gln Asp

100 105 110

Ala Pro Pro Leu Pro Val Pro Gly Val Leu Leu Lys Glu Phe Thr Val

115 120 125

Ser Gly Asn Ile Leu Thr Ile Arg Leu Thr Ala Ala Asp His Arg Gln

130 135 140

Leu Gln Leu Ser Ile Ser Ser Cys Leu Gln Gln Leu Ser Leu Leu Met

145 150 155 160

Trp Ile Thr Gln Cys Phe Leu Pro Val Phe Leu Ala Gln Pro Pro Ser

165 170 175

Gly Gln Arg Arg

180

<210> 357

<211> 852

<212> PRT

<213> Artificial sequence

<220>

<223> PIWIL-4

<400> 357

Met Ser Gly Arg Ala Arg Val Lys Ala Arg Gly Ile Ala Arg Ser Pro

1 5 10 15

Ser Ala Thr Glu Val Gly Arg Ile Gln Ala Ser Pro Leu Pro Arg Ser

20 25 30

Val Asp Leu Ser Asn Asn Glu Ala Ser Ser Ser Asn Gly Phe Leu Gly

35 40 45

Thr Ser Arg Ile Ser Thr Asn Asp Lys Tyr Gly Ile Ser Ser Gly Asp

50 55 60

Ala Gly Ser Thr Phe Met Glu Arg Gly Val Lys Asn Lys Gln Asp Phe

65 70 75 80

Met Asp Leu Ser Ile Cys Thr Arg Glu Lys Leu Ala His Val Arg Asn

85 90 95

Cys Lys Thr Gly Ser Ser Gly Ile Pro Val Lys Leu Val Thr Asn Leu

100 105 110

Phe Asn Leu Asp Phe Pro Gln Asp Trp Gln Leu Tyr Gln Tyr His Val

115 120 125

Thr Tyr Ile Pro Asp Leu Ala Ser Arg Arg Leu Arg Ile Ala Leu Leu

130 135 140

Tyr Ser His Ser Glu Leu Ser Asn Lys Ala Lys Ala Phe Asp Gly Ala

145 150 155 160

Ile Leu Phe Leu Ser Gln Lys Leu Glu Glu Lys Val Thr Glu Leu Ser

165 170 175

Ser Glu Thr Gln Arg Gly Glu Thr Ile Lys Met Thr Ile Thr Leu Lys

180 185 190

Arg Glu Leu Pro Ser Ser Ser Pro Val Cys Ile Gln Val Phe Asn Ile

195 200 205

Ile Phe Arg Lys Ile Leu Lys Lys Leu Ser Met Tyr Gln Ile Gly Arg

210 215 220

Asn Phe Tyr Asn Pro Ser Glu Pro Met Glu Ile Pro Gln His Lys Leu

225 230 235 240

Ser Leu Trp Pro Gly Phe Ala Ile Ser Val Ser Tyr Phe Glu Arg Lys

245 250 255

Leu Leu Phe Ser Ala Asp Val Ser Tyr Lys Val Leu Arg Asn Glu Thr

260 265 270

Val Leu Glu Phe Met Thr Ala Leu Cys Gln Arg Thr Gly Leu Ser Cys

275 280 285

Phe Thr Gln Thr Cys Glu Lys Gln Leu Ile Gly Leu Ile Val Leu Thr

290 295 300

Arg Tyr Asn Asn Arg Thr Tyr Ser Ile Asp Asp Ile Asp Trp Ser Val

305 310 315 320

Lys Pro Thr His Thr Phe Gln Lys Arg Asp Gly Thr Glu Ile Thr Tyr

325 330 335

Val Asp Tyr Tyr Lys Gln Gln Tyr Asp Ile Thr Val Ser Asp Leu Asn

340 345 350

Gln Pro Met Leu Val Ser Leu Leu Lys Lys Lys Arg Asn Asp Asn Ser

355 360 365

Glu Ala Gln Leu Ala His Leu Ile Pro Glu Leu Cys Phe Leu Thr Gly

370 375 380

Leu Thr Asp Gln Ala Thr Ser Asp Phe Gln Leu Met Lys Ala Val Ala

385 390 395 400

Glu Lys Thr Arg Leu Ser Pro Ser Gly Arg Gln Gln Arg Leu Ala Arg

405 410 415

Leu Val Asp Asn Ile Gln Arg Asn Thr Asn Ala Arg Phe Glu Leu Glu

420 425 430

Thr Trp Gly Leu His Phe Gly Ser Gln Ile Ser Leu Thr Gly Arg Ile

435 440 445

Val Pro Ser Glu Lys Ile Leu Met Gln Asp His Ile Cys Gln Pro Val

450 455 460

Ser Ala Ala Asp Trp Ser Lys Asp Ile Arg Thr Cys Lys Ile Leu Asn

465 470 475 480

Ala Gln Ser Leu Asn Thr Trp Leu Ile Leu Cys Ser Asp Arg Thr Glu

485 490 495

Tyr Val Ala Glu Ser Phe Leu Asn Cys Leu Arg Arg Val Ala Gly Ser

500 505 510

Met Gly Phe Asn Val Asp Tyr Pro Lys Ile Ile Lys Val Gln Glu Asn

515 520 525

Pro Ala Ala Phe Val Arg Ala Ile Gln Gln Tyr Val Asp Pro Asp Val

530 535 540

Gln Leu Val Met Cys Ile Leu Pro Ser Asn Gln Lys Thr Tyr Tyr Asp

545 550 555 560

Ser Ile Lys Lys Tyr Leu Ser Ser Asp Cys Pro Val Pro Ser Gln Cys

565 570 575

Val Leu Ala Arg Thr Leu Asn Lys Gln Gly Met Met Met Ser Ile Ala

580 585 590

Thr Lys Ile Ala Met Gln Met Thr Cys Lys Leu Gly Gly Glu Leu Trp

595 600 605

Ala Val Glu Ile Pro Leu Lys Ser Leu Met Val Val Gly Ile Asp Val

610 615 620

Cys Lys Asp Ala Leu Ser Lys Asp Val Met Val Val Gly Cys Val Ala

625 630 635 640

Ser Val Asn Pro Arg Ile Thr Arg Trp Phe Ser Arg Cys Ile Leu Gln

645 650 655

Arg Thr Met Thr Asp Val Ala Asp Cys Leu Lys Val Phe Met Thr Gly

660 665 670

Ala Leu Asn Lys Trp Tyr Lys Tyr Asn His Asp Leu Pro Ala Arg Ile

675 680 685

Ile Val Tyr Arg Ala Gly Val Gly Asp Gly Gln Leu Lys Thr Leu Ile

690 695 700

Glu Tyr Glu Val Pro Gln Leu Leu Ser Ser Val Ala Glu Ser Ser Ser

705 710 715 720

Asn Thr Ser Ser Arg Leu Ser Val Ile Val Val Arg Lys Lys Cys Met

725 730 735

Pro Arg Phe Phe Thr Glu Met Asn Arg Thr Val Gln Asn Pro Pro Leu

740 745 750

Gly Thr Val Val Asp Ser Glu Ala Thr Arg Asn Glu Trp Tyr Asp Phe

755 760 765

Tyr Leu Ile Ser Gln Val Ala Cys Arg Gly Thr Val Ser Pro Thr Tyr

770 775 780

Tyr Asn Val Ile Tyr Asp Asp Asn Gly Leu Lys Pro Asp His Met Gln

785 790 795 800

Arg Leu Thr Phe Lys Leu Cys His Leu Tyr Tyr Asn Trp Pro Gly Ile

805 810 815

Val Ser Val Pro Ala Pro Cys Gln Tyr Ala His Lys Leu Thr Phe Leu

820 825 830

Val Ala Gln Ser Ile His Lys Glu Pro Ser Leu Glu Leu Ala Asn His

835 840 845

Leu Phe Tyr Leu

850

<210> 358

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<223> WT1

<400> 358

Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Pro

1 5 10 15

Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala Ala

20 25 30

Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr

35 40 45

Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro Pro

50 55 60

Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly

65 70 75 80

Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe

85 90 95

Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe

100 105 110

Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe

115 120 125

Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gln Pro Ala Ile

130 135 140

Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr

145 150 155 160

Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe

165 170 175

Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln

180 185 190

Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser

195 200 205

Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp

210 215 220

Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln

225 230 235 240

Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala Gly Ser Ser Ser

245 250 255

Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Ser Thr Gly Tyr Glu

260 265 270

Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile

275 280 285

His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro

290 295 300

Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys

305 310 315 320

Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys

325 330 335

Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro

340 345 350

Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp

355 360 365

Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln

370 375 380

Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr

385 390 395 400

His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser Cys

405 410 415

Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val

420 425 430

Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala

435 440 445

Leu

<210> 359

<211> 543

<212> PRT

<213> Artificial sequence

<220>

<223> OY-TES-1

<400> 359

Met Arg Lys Pro Ala Ala Gly Phe Leu Pro Ser Leu Leu Lys Val Leu

1 5 10 15

Leu Leu Pro Leu Ala Pro Ala Ala Ala Gln Asp Ser Thr Gln Ala Ser

20 25 30

Thr Pro Gly Ser Pro Leu Ser Pro Thr Glu Tyr Glu Arg Phe Phe Ala

35 40 45

Leu Leu Thr Pro Thr Trp Lys Ala Glu Thr Thr Cys Arg Leu Arg Ala

50 55 60

Thr His Gly Cys Arg Asn Pro Thr Leu Val Gln Leu Asp Gln Tyr Glu

65 70 75 80

Asn His Gly Leu Val Pro Asp Gly Ala Val Cys Ser Asn Leu Pro Tyr

85 90 95

Ala Ser Trp Phe Glu Ser Phe Cys Gln Phe Thr His Tyr Arg Cys Ser

100 105 110

Asn His Val Tyr Tyr Ala Lys Arg Val Leu Cys Ser Gln Pro Val Ser

115 120 125

Ile Leu Ser Pro Asn Thr Leu Lys Glu Ile Glu Ala Ser Ala Glu Val

130 135 140

Ser Pro Thr Thr Met Thr Ser Pro Ile Ser Pro His Phe Thr Val Thr

145 150 155 160

Glu Arg Gln Thr Phe Gln Pro Trp Pro Glu Arg Leu Ser Asn Asn Val

165 170 175

Glu Glu Leu Leu Gln Ser Ser Leu Ser Leu Gly Gly Gln Glu Gln Ala

180 185 190

Pro Glu His Lys Gln Glu Gln Gly Val Glu His Arg Gln Glu Pro Thr

195 200 205

Gln Glu His Lys Gln Glu Glu Gly Gln Lys Gln Glu Glu Gln Glu Glu

210 215 220

Glu Gln Glu Glu Glu Gly Lys Gln Glu Glu Gly Gln Gly Thr Lys Glu

225 230 235 240

Gly Arg Glu Ala Val Ser Gln Leu Gln Thr Asp Ser Glu Pro Lys Phe

245 250 255

His Ser Glu Ser Leu Ser Ser Asn Pro Ser Ser Phe Ala Pro Arg Val

260 265 270

Arg Glu Val Glu Ser Thr Pro Met Ile Met Glu Asn Ile Gln Glu Leu

275 280 285

Ile Arg Ser Ala Gln Glu Ile Asp Glu Met Asn Glu Ile Tyr Asp Glu

290 295 300

Asn Ser Tyr Trp Arg Asn Gln Asn Pro Gly Ser Leu Leu Gln Leu Pro

305 310 315 320

His Thr Glu Ala Leu Leu Val Leu Cys Tyr Ser Ile Val Glu Asn Thr

325 330 335

Cys Ile Ile Thr Pro Thr Ala Lys Ala Trp Lys Tyr Met Glu Glu Glu

340 345 350

Ile Leu Gly Phe Gly Lys Ser Val Cys Asp Ser Leu Gly Arg Arg His

355 360 365

Met Ser Thr Cys Ala Leu Cys Asp Phe Cys Ser Leu Lys Leu Glu Gln

370 375 380

Cys His Ser Glu Ala Ser Leu Gln Arg Gln Gln Cys Asp Thr Ser His

385 390 395 400

Lys Thr Pro Phe Val Ser Pro Leu Leu Ala Ser Gln Ser Leu Ser Ile

405 410 415

Gly Asn Gln Val Gly Ser Pro Glu Ser Gly Arg Phe Tyr Gly Leu Asp

420 425 430

Leu Tyr Gly Gly Leu His Met Asp Phe Trp Cys Ala Arg Leu Ala Thr

435 440 445

Lys Gly Cys Glu Asp Val Arg Val Ser Gly Trp Leu Gln Thr Glu Phe

450 455 460

Leu Ser Phe Gln Asp Gly Asp Phe Pro Thr Lys Ile Cys Asp Thr Asp

465 470 475 480

Tyr Ile Gln Tyr Pro Asn Tyr Cys Ser Phe Lys Ser Gln Gln Cys Leu

485 490 495

Met Arg Asn Arg Asn Arg Lys Val Ser Arg Met Arg Cys Leu Gln Asn

500 505 510

Glu Thr Tyr Ser Ala Leu Ser Pro Gly Lys Ser Glu Asp Val Val Leu

515 520 525

Arg Trp Ser Gln Glu Phe Ser Thr Leu Thr Leu Gly Gln Phe Gly

530 535 540

<210> 360

<211> 882

<212> PRT

<213> Artificial sequence

<220>

<223> PIWIL-3

<400> 360

Met Pro Gly Arg Ala Arg Thr Arg Ala Arg Gly Arg Ala Arg Arg Arg

1 5 10 15

Glu Ser Tyr Gln Gln Glu Ala Pro Gly Gly Pro Arg Ala Pro Gly Ser

20 25 30

Ala Thr Thr Gln Glu Pro Pro Gln Leu Gln Ser Thr Pro Arg Pro Leu

35 40 45

Gln Glu Glu Val Pro Val Val Arg Pro Leu Gln Pro Arg Ala Ala Arg

50 55 60

Gly Gly Ala Gly Gly Gly Ala Gln Ser Gln Gly Val Lys Glu Pro Gly

65 70 75 80

Pro Glu Ala Gly Leu His Thr Ala Pro Leu Gln Glu Arg Arg Ile Gly

85 90 95

Gly Val Phe Gln Asp Leu Val Val Asn Thr Arg Gln Asp Met Lys His

100 105 110

Val Lys Asp Ser Lys Thr Gly Ser Glu Gly Thr Val Val Gln Leu Leu

115 120 125

Ala Asn His Phe Arg Val Ile Ser Arg Pro Gln Trp Val Ala Tyr Lys

130 135 140

Tyr Asn Val Asp Tyr Lys Pro Asp Ile Glu Asp Gly Asn Leu Arg Thr

145 150 155 160

Ile Leu Leu Asp Gln His Arg Arg Lys Phe Gly Glu Arg His Ile Phe

165 170 175

Asp Gly Asn Ser Leu Leu Leu Ser Arg Pro Leu Lys Glu Arg Arg Val

180 185 190

Glu Trp Leu Ser Thr Thr Lys Asp Lys Asn Ile Val Lys Ile Thr Val

195 200 205

Glu Phe Ser Lys Glu Leu Thr Pro Thr Ser Pro Asp Cys Leu Arg Tyr

210 215 220

Tyr Asn Ile Leu Phe Arg Arg Thr Phe Lys Leu Leu Asp Phe Glu Gln

225 230 235 240

Val Gly Arg Asn Tyr Tyr Thr Lys Lys Lys Ala Ile Gln Leu Tyr Arg

245 250 255

His Gly Thr Ser Leu Glu Ile Trp Leu Gly Tyr Val Thr Ser Val Leu

260 265 270

Gln Tyr Glu Asn Ser Ile Thr Leu Cys Ala Asp Val Ser His Lys Leu

275 280 285

Leu Arg Ile Glu Thr Ala Tyr Asp Phe Ile Lys Arg Thr Ser Ala Gln

290 295 300

Ala Gln Thr Gly Asn Ile Arg Glu Glu Val Thr Asn Lys Leu Ile Gly

305 310 315 320

Ser Ile Val Leu Thr Lys Tyr Asn Asn Lys Thr Tyr Arg Val Asp Asp

325 330 335

Ile Asp Trp Lys Gln Asn Pro Glu Asp Thr Phe Asn Lys Ser Asp Gly

340 345 350

Ser Lys Ile Thr Tyr Ile Asp Tyr Tyr Arg Gln Gln His Lys Glu Ile

355 360 365

Val Thr Val Lys Lys Gln Pro Leu Leu Val Ser Gln Gly Arg Trp Lys

370 375 380

Lys Gly Leu Thr Gly Thr Gln Arg Glu Pro Ile Leu Leu Ile Pro Gln

385 390 395 400

Leu Cys His Met Thr Gly Leu Thr Asp Glu Ile Cys Lys Asp Tyr Ser

405 410 415

Ile Val Lys Glu Leu Ala Lys His Thr Arg Leu Ser Pro Arg Arg Arg

420 425 430

His His Thr Leu Lys Glu Phe Ile Asn Thr Leu Gln Asp Asn Lys Lys

435 440 445

Val Arg Glu Leu Leu Gln Leu Trp Asp Leu Lys Phe Asp Thr Asn Phe

450 455 460

Leu Ser Val Pro Gly Arg Val Leu Lys Asn Ala Asn Ile Val Gln Gly

465 470 475 480

Arg Arg Met Val Lys Ala Asn Ser Gln Gly Asp Trp Ser Arg Glu Ile

485 490 495

Arg Glu Leu Pro Leu Leu Asn Ala Met Pro Leu His Ser Trp Leu Ile

500 505 510

Leu Tyr Ser Arg Ser Ser His Arg Glu Ala Met Ser Leu Lys Gly His

515 520 525

Leu Gln Ser Val Thr Ala Pro Met Gly Ile Thr Met Lys Pro Ala Glu

530 535 540

Met Ile Glu Val Asp Gly Asp Ala Asn Ser Tyr Ile Asp Thr Leu Arg

545 550 555 560

Lys Tyr Thr Arg Pro Thr Leu Gln Met Gly Met Ser Cys Leu Leu Val

565 570 575

Phe Lys Val Ile Cys Ile Leu Pro Asn Asp Asp Lys Arg Arg Tyr Asp

580 585 590

Ser Ile Lys Arg Tyr Leu Cys Thr Lys Cys Pro Ile Pro Ser Gln Cys

595 600 605

Val Val Lys Lys Thr Leu Glu Lys Val Gln Ala Arg Thr Ile Val Thr

610 615 620

Lys Ile Ala Gln Gln Met Asn Cys Lys Met Gly Gly Ala Leu Trp Lys

625 630 635 640

Val Glu Thr Asp Val Gln Arg Thr Met Phe Val Gly Ile Asp Cys Phe

645 650 655

His Asp Ile Val Asn Arg Gln Lys Ser Ile Ala Gly Phe Val Ala Ser

660 665 670

Thr Asn Ala Glu Leu Thr Lys Trp Tyr Ser Gln Cys Val Ile Gln Lys

675 680 685

Thr Gly Glu Glu Leu Val Lys Glu Leu Glu Ile Cys Leu Lys Ala Ala

690 695 700

Leu Asp Val Trp Cys Lys Asn Glu Ser Ser Met Pro His Ser Val Ile

705 710 715 720

Val Tyr Arg Asp Gly Val Gly Asp Gly Gln Leu Gln Ala Leu Leu Asp

725 730 735

His Glu Ala Lys Lys Met Ser Thr Tyr Leu Lys Thr Ile Ser Pro Asn

740 745 750

Asn Phe Thr Leu Ala Phe Ile Val Val Lys Lys Arg Ile Asn Thr Arg

755 760 765

Phe Phe Leu Lys His Gly Ser Asn Phe Gln Asn Pro Pro Pro Gly Thr

770 775 780

Val Ile Asp Val Glu Leu Thr Arg Asn Glu Trp Tyr Asp Phe Phe Ile

785 790 795 800

Val Ser Gln Ser Val Gln Asp Gly Thr Val Thr Pro Thr His Tyr Asn

805 810 815

Val Ile Tyr Asp Thr Ile Gly Leu Ser Pro Asp Thr Val Gln Arg Leu

820 825 830

Thr Tyr Cys Leu Cys His Met Tyr Tyr Asn Leu Pro Gly Ile Ile Arg

835 840 845

Val Pro Ala Pro Cys His Tyr Ala His Lys Leu Ala Tyr Leu Val Gly

850 855 860

Gln Ser Ile His Gln Glu Pro Asn Arg Ser Leu Ser Thr Arg Leu Phe

865 870 875 880

Tyr Leu

<210> 361

<211> 853

<212> PRT

<213> Artificial sequence

<220>

<223> AKAP3

<400> 361

Met Ser Glu Lys Val Asp Trp Leu Gln Ser Gln Asn Gly Val Cys Lys

1 5 10 15

Val Asp Val Tyr Ser Pro Gly Asp Asn Gln Ala Gln Asp Trp Lys Met

20 25 30

Asp Thr Ser Thr Asp Pro Val Arg Val Leu Ser Trp Leu Arg Arg Asp

35 40 45

Leu Glu Lys Ser Thr Ala Glu Phe Gln Asp Val Arg Phe Lys Pro Gly

50 55 60

Glu Ser Phe Gly Gly Glu Thr Ser Asn Ser Gly Asp Pro His Lys Gly

65 70 75 80

Phe Ser Val Asp Tyr Tyr Asn Thr Thr Thr Lys Gly Thr Pro Glu Arg

85 90 95

Leu His Phe Glu Met Thr His Lys Glu Ile Pro Cys Gln Gly Pro Arg

100 105 110

Ala Gln Leu Gly Asn Gly Ser Ser Val Asp Glu Val Ser Phe Tyr Ala

115 120 125

Asn Arg Leu Thr Asn Leu Val Ile Ala Met Ala Arg Lys Glu Ile Asn

130 135 140

Glu Lys Ile Asp Gly Ser Glu Asn Lys Cys Val Tyr Gln Ser Leu Tyr

145 150 155 160

Met Gly Asn Glu Pro Thr Pro Thr Lys Ser Leu Ser Lys Ile Ala Ser

165 170 175

Glu Leu Val Asn Glu Thr Val Ser Ala Cys Ser Arg Asn Ala Ala Pro

180 185 190

Asp Lys Ala Pro Gly Ser Gly Asp Arg Val Ser Gly Ser Ser Gln Ser

195 200 205

Pro Pro Asn Leu Lys Tyr Lys Ser Thr Leu Lys Ile Lys Glu Ser Thr

210 215 220

Lys Glu Arg Gln Gly Pro Asp Asp Lys Pro Pro Ser Lys Lys Ser Phe

225 230 235 240

Phe Tyr Lys Glu Val Phe Glu Ser Arg Asn Gly Asp Tyr Ala Arg Glu

245 250 255

Gly Gly Arg Phe Phe Pro Arg Glu Arg Lys Arg Phe Arg Gly Gln Glu

260 265 270

Arg Pro Asp Asp Phe Thr Ala Ser Val Ser Glu Gly Ile Met Thr Tyr

275 280 285

Ala Asn Ser Val Val Ser Asp Met Met Val Ser Ile Met Lys Thr Leu

290 295 300

Lys Ile Gln Val Lys Asp Thr Thr Ile Ala Thr Ile Leu Leu Lys Lys

305 310 315 320

Val Leu Leu Lys His Ala Lys Glu Val Val Ser Asp Leu Ile Asp Ser

325 330 335

Phe Leu Arg Asn Leu His Ser Val Thr Gly Thr Leu Met Thr Asp Thr

340 345 350

Gln Phe Val Ser Ala Val Lys Arg Thr Val Phe Ser His Gly Ser Gln

355 360 365

Lys Ala Thr Asp Ile Met Asp Ala Met Leu Arg Lys Leu Tyr Asn Val

370 375 380

Met Phe Ala Lys Lys Val Pro Glu His Val Arg Lys Ala Gln Asp Lys

385 390 395 400

Ala Glu Ser Tyr Ser Leu Ile Ser Met Lys Gly Met Gly Asp Pro Lys

405 410 415

Asn Arg Asn Val Asn Phe Ala Met Lys Ser Glu Thr Lys Leu Arg Glu

420 425 430

Lys Met Tyr Ser Glu Pro Lys Ser Glu Glu Glu Thr Cys Ala Lys Thr

435 440 445

Leu Gly Glu His Ile Ile Lys Glu Gly Leu Thr Leu Trp His Lys Thr

450 455 460

Gln Gln Lys Glu Cys Lys Ser Leu Gly Phe Gln His Ala Ala Phe Glu

465 470 475 480

Ala Pro Asn Thr Gln Arg Lys Pro Ala Ser Asp Ile Ser Phe Glu Tyr

485 490 495

Pro Glu Asp Ile Gly Asn Leu Ser Leu Pro Pro Tyr Pro Pro Glu Lys

500 505 510

Pro Glu Asn Phe Met Tyr Asp Ser Asp Ser Trp Ala Glu Asp Leu Ile

515 520 525

Val Ser Ala Leu Leu Leu Ile Gln Tyr His Leu Ala Gln Gly Gly Arg

530 535 540

Arg Asp Ala Arg Ser Phe Val Glu Ala Ala Gly Thr Thr Asn Phe Pro

545 550 555 560

Ala Asn Glu Pro Pro Val Ala Pro Asp Glu Ser Cys Leu Lys Ser Ala

565 570 575

Pro Ile Val Gly Asp Gln Glu Gln Ala Glu Lys Lys Asp Leu Arg Ser

580 585 590

Val Phe Phe Asn Phe Ile Arg Asn Leu Leu Ser Glu Thr Ile Phe Lys

595 600 605

Arg Asp Gln Ser Pro Glu Pro Lys Val Pro Glu Gln Pro Val Lys Glu

610 615 620

Asp Arg Lys Leu Cys Glu Arg Pro Leu Ala Ser Ser Pro Pro Arg Leu

625 630 635 640

Tyr Glu Asp Asp Glu Thr Pro Gly Ala Leu Ser Gly Leu Thr Lys Met

645 650 655

Ala Val Ser Gln Ile Asp Gly His Met Ser Gly Gln Met Val Glu His

660 665 670

Leu Met Asn Ser Val Met Lys Leu Cys Val Ile Ile Ala Lys Ser Cys

675 680 685

Asp Ala Ser Leu Ala Glu Leu Gly Asp Asp Lys Ser Gly Asp Ala Ser

690 695 700

Arg Leu Thr Ser Ala Phe Pro Asp Ser Leu Tyr Glu Cys Leu Pro Ala

705 710 715 720

Lys Gly Thr Gly Ser Ala Glu Ala Val Leu Gln Asn Ala Tyr Gln Ala

725 730 735

Ile His Asn Glu Met Arg Gly Thr Ser Gly Gln Pro Pro Glu Gly Cys

740 745 750

Ala Ala Pro Thr Val Ile Val Ser Asn His Asn Leu Thr Asp Thr Val

755 760 765

Gln Asn Lys Gln Leu Gln Ala Val Leu Gln Trp Val Ala Ala Ser Glu

770 775 780

Leu Asn Val Pro Ile Leu Tyr Phe Ala Gly Asp Asp Glu Gly Ile Gln

785 790 795 800

Glu Lys Leu Leu Gln Leu Ser Ala Ala Ala Val Asp Lys Gly Cys Ser

805 810 815

Val Gly Glu Val Leu Gln Ser Val Leu Arg Tyr Glu Lys Glu Arg Gln

820 825 830

Leu Asn Glu Ala Val Gly Asn Val Thr Pro Leu Gln Leu Leu Asp Trp

835 840 845

Leu Met Val Asn Leu

850

<210> 362

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 1

<400> 362

Asn Ser Leu Gln Lys Gln Leu Gln Ala Val Leu Gln Trp Ile Ala Ala

1 5 10 15

Ser Gln Phe Asn

20

<210> 363

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 2

<400> 363

Ser Gly Asp Glu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser

1 5 10 15

Asn Val Glu Glu

20

<210> 364

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 3

<400> 364

Val Gln Lys Glu Asp Gly Arg Val Gln Ala Phe Gly Trp Ser Leu Pro

1 5 10 15

Gln Lys Tyr Lys

20

<210> 365

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 4

<400> 365

Glu Val Glu Ser Thr Pro Met Ile Met Glu Asn Ile Gln Glu Leu Ile

1 5 10 15

Arg Ser Ala Gln

20

<210> 366

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 5

<400> 366

Ala Tyr Phe Glu Ser Leu Leu Glu Lys Arg Glu Lys Thr Asn Phe Asp

1 5 10 15

Pro Ala Glu Trp

20

<210> 367

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 6

<400> 367

Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe Pro Asn Ala Pro

1 5 10 15

Tyr Leu Pro Ser

20

<210> 368

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 7

<400> 368

Arg Arg Ser Ile Ala Gly Phe Val Ala Ser Ile Asn Glu Gly Met Thr

1 5 10 15

Arg Trp Phe Ser

20

<210> 369

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 8

<400> 369

Met Gln Asp Ile Lys Met Ile Leu Lys Met Val Gln Leu Asp Ser Ile

1 5 10 15

Glu Asp Leu Glu

20

<210> 370

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 9

<400> 370

Ala Asn Ser Val Val Ser Asp Met Met Val Ser Ile Met Lys Thr Leu

1 5 10 15

Lys Ile Gln Val

20

<210> 371

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 10

<400> 371

Arg Glu Ala Leu Ser Asn Lys Val Asp Glu Leu Ala His Phe Leu Leu

1 5 10 15

Arg Lys Tyr Arg

20

<210> 372

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 11

<400> 372

Glu Thr Ser Tyr Glu Lys Val Ile Asn Tyr Leu Val Met Leu Asn Ala

1 5 10 15

Arg Glu Pro Ile

20

<210> 373

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 12

<400> 373

Asp Val Lys Glu Val Asp Pro Thr Gly His Ser Phe Val Leu Val Thr

1 5 10 15

Ser Le Gly Le

20

<210> 374

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> XYZ 13

<400> 374

Ser Ala Gln Leu Leu Gln Ala Arg Leu Met Lys Glu Glu Ser Pro Val

1 5 10 15

Val Ser Trp Arg

20

<210> 375

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 1

<400> 375

Ile Ser Asp Thr Lys Asp Tyr Phe Met Ser Lys Thr Leu Gly Ile Gly

1 5 10 15

Arg Leu Lys Arg

20

<210> 376

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 2

<400> 376

Phe Asp Arg Asn Thr Glu Ser Leu Phe Glu Glu Leu Ser Ser Ala Gly

1 5 10 15

Ser Gly Leu Ile

20

<210> 377

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 3

<400> 377

Ser Gln Lys Met Asp Met Ser Asn Ile Val Leu Met Leu Ile Gln Lys

1 5 10 15

Leu Leu Asn Glu

20

<210> 378

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 4

<400> 378

Ser Ala Val Phe His Glu Arg Tyr Ala Leu Ile Gln His Gln Lys Thr

1 5 10 15

His Lys Asn Glu

20

<210> 379

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 5

<400> 379

Asp Val Lys Glu Val Asp Pro Thr Ser His Ser Tyr Val Leu Val Thr

1 5 10 15

Ser Leu Asn Leu

20

<210> 380

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 6

<400> 380

Glu Asn Ala His Gly Gln Ser Leu Glu Glu Asp Ser Ala Leu Glu Ala

1 5 10 15

Leu Leu Asn Phe

20

<210> 381

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 7

<400> 381

Met Ala Ser Phe Arg Lys Leu Thr Leu Ser Glu Lys Val Pro Pro Asn

1 5 10 15

His Pro Ser Arg

20

<210> 382

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 8

<400> 382

Lys Arg Ala Ser Gln Tyr Ser Gly Gln Leu Lys Val Leu Ile Ala Glu

1 5 10 15

Asn Thr Met Leu

20

<210> 383

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 9

<400> 383

Val Asp Pro Ala Gln Leu Glu Phe Met Phe Gln Glu Ala Leu Lys Leu

1 5 10 15

Lys Val Ala Glu

20

<210> 384

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 10

<400> 384

Glu Tyr Glu Arg Glu Glu Thr Arg Gln Val Tyr Met Asp Leu Asn Asn

1 5 10 15

Asn Ile Glu Lys

20

<210> 385

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 11

<400> 385

Pro Glu Ile Phe Gly Lys Ala Ser Glu Ser Leu Gln Leu Val Phe Gly

1 5 10 15

Ile Asp Val Lys

20

<210> 386

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<223> ABC 12

<400> 386

Asp Ser Glu Ser Ser Phe Thr Tyr Thr Leu Asp Glu Lys Val Ala Glu

1 5 10 15

Leu Val Glu Phe

20

<210> 387

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 1

<400> 387

Gln Phe Pro Val Ser Glu Gly Lys Ser

1 5

<210> 388

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 2

<400> 388

Phe Pro Val Ser Glu Gly Lys Ser Arg

1 5

<210> 389

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 3

<400> 389

Pro Val Ser Glu Gly Lys Ser Arg Tyr

1 5

<210> 390

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 4

<400> 390

Val Ser Glu Gly Lys Ser Arg Tyr Arg

1 5

<210> 391

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 5

<400> 391

Ser Glu Gly Lys Ser Arg Tyr Arg Ala

1 5

<210> 392

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 6

<400> 392

Glu Gly Lys Ser Arg Tyr Arg Ala Gln

1 5

<210> 393

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 7

<400> 393

Gly Lys Ser Arg Tyr Arg Ala Gln Arg

1 5

<210> 394

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P1 8

<400> 394

Lys Ser Arg Tyr Arg Ala Gln Arg Phe

1 5

<210> 395

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 1

<400> 395

Ile Glu Leu Lys His Lys Ala Arg Thr

1 5

<210> 396

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 2

<400> 396

Glu Leu Lys His Lys Ala Arg Thr Ala

1 5

<210> 397

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 3

<400> 397

Leu Lys His Lys Ala Arg Thr Ala Lys

1 5

<210> 398

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 4

<400> 398

Lys His Lys Ala Arg Thr Ala Lys Lys

1 5

<210> 399

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 5

<400> 399

His Lys Ala Arg Thr Ala Lys Lys Val

1 5

<210> 400

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 6

<400> 400

Lys Ala Arg Thr Ala Lys Lys Val Arg

1 5

<210> 401

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 7

<400> 401

Ala Arg Thr Ala Lys Lys Val Arg Arg

1 5

<210> 402

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P2 8

<400> 402

Arg Thr Ala Lys Lys Val Arg Arg Ala

1 5

<210> 403

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 1

<400> 403

Glu Phe Ser Met Gln Gly Leu Lys Asp

1 5

<210> 404

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 2

<400> 404

Phe Ser Met Gln Gly Leu Lys Asp Glu

1 5

<210> 405

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> SMQGLKDEK

<400> 405

Ser Met Gln Gly Leu Lys Asp Glu Lys

1 5

<210> 406

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 4

<400> 406

Met Gln Gly Leu Lys Asp Glu Lys Val

1 5

<210> 407

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 5

<400> 407

Gln Gly Leu Lys Asp Glu Lys Val Ala

1 5

<210> 408

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 6

<400> 408

Gly Leu Lys Asp Glu Lys Val Ala Glu

1 5

<210> 409

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 7

<400> 409

Leu Lys Asp Glu Lys Val Ala Glu Leu

1 5

<210> 410

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P3 8

<400> 410

Lys Asp Glu Lys Val Ala Glu Leu Val

1 5

<210> 411

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 1

<400> 411

Leu Leu Ala Leu Met Val Gly Leu Lys

1 5

<210> 412

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 2

<400> 412

Leu Ala Leu Met Val Gly Leu Lys Asp

1 5

<210> 413

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 3

<400> 413

Ala Leu Met Val Gly Leu Lys Asp His

1 5

<210> 414

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 4

<400> 414

Leu Met Val Gly Leu Lys Asp His Arg

1 5

<210> 415

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 5

<400> 415

Met Val Gly Leu Lys Asp His Arg Ile

1 5

<210> 416

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 6

<400> 416

Val Gly Leu Lys Asp His Arg Ile Ser

1 5

<210> 417

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 7

<400> 417

Gly Leu Lys Asp His Arg Ile Ser Thr

1 5

<210> 418

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P6 8

<400> 418

Leu Lys Asp His Arg Ile Ser Thr Phe

1 5

<210> 419

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 1

<400> 419

Pro Ala Leu Phe Lys Glu Asn Arg Ser

1 5

<210> 420

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 2

<400> 420

Ala Leu Phe Lys Glu Asn Arg Ser Gly

1 5

<210> 421

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 3

<400> 421

Leu Phe Lys Glu Asn Arg Ser Gly Ala

1 5

<210> 422

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 4

<400> 422

Phe Lys Glu Asn Arg Ser Gly Ala Val

1 5

<210> 423

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 5

<400> 423

Lys Glu Asn Arg Ser Gly Ala Val Met

1 5

<210> 424

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 6

<400> 424

Glu Asn Arg Ser Gly Ala Val Met Ser

1 5

<210> 425

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 7

<400> 425

Asn Arg Ser Gly Ala Val Met Ser Glu

1 5

<210> 426

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P7 8

<400> 426

Arg Ser Gly Ala Val Met Ser Glu Arg

1 5

<210> 427

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 1

<400> 427

Ala Val Leu Thr Lys Lys Phe Gln Lys

1 5

<210> 428

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 2

<400> 428

Val Leu Thr Lys Lys Phe Gln Lys Val

1 5

<210> 429

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 3

<400> 429

Leu Thr Lys Lys Phe Gln Lys Val Asn

1 5

<210> 430

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 4

<400> 430

Thr Lys Lys Phe Gln Lys Val Asn Phe

1 5

<210> 431

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 5

<400> 431

Lys Lys Phe Gln Lys Val Asn Phe Phe

1 5

<210> 432

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 6

<400> 432

Lys Phe Gln Lys Val Asn Phe Phe Phe

1 5

<210> 433

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 7

<400> 433

Phe Gln Lys Val Asn Phe Phe Phe Glu

1 5

<210> 434

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> CRC-P8 8

<400> 434

Gln Lys Val Asn Phe Phe Phe Glu Arg

1 5

<210> 435

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-1

<400> 435

Tyr Ser Ser Asn Ala Tyr His Met Ser Ser Thr Met Lys Pro Asn Phe

1 5 10 15

Val Ala Ser Ile Asn Leu Thr Leu Thr Lys Trp Tyr Ser Arg

20 25 30

<210> 436

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-2

<400> 436

Arg Asn Phe Tyr Asp Pro Thr Ser Ala Met Val Leu Gln Gln His Met

1 5 10 15

Met Ala Tyr Ser Asp Thr Thr Met Met Ser Asp Asp Ile Asp

20 25 30

<210> 437

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-3

<400> 437

Leu Arg Tyr Arg Tyr Thr Leu Asp Asp Leu Tyr Pro Met Met Asn Ser

1 5 10 15

Asp Tyr Ala Val His Pro Met Ser Pro Val Gly Arg Thr Ser

20 25 30

<210> 438

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-4

<400> 438

Ser Gly Ala Val Met Ser Glu Arg Val Ser Gly Leu Ala Gly Ser Arg

1 5 10 15

Thr Tyr Trp Ile Ile Ile Glu Leu Lys His Lys Ala Arg Glu

20 25 30

<210> 439

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-5

<400> 439

Asp Leu Ser Phe Tyr Val Asn Arg Leu Ser Ser Leu Val Ile Gln Asn

1 5 10 15

Arg Thr Ser Tyr Leu His Ser Pro Phe Ser Thr Gly Arg Ser

20 25 30

<210> 440

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-6

<400> 440

Val Asn Ile Asp Tyr Leu Met Asn Arg Pro Gln Asn Leu Arg Leu His

1 5 10 15

Ala Phe Asp Gly Thr Ile Leu Phe Leu Pro Lys Arg Leu Gln

20 25 30

<210> 441

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-7

<400> 441

Ser Asp Leu Gln Lys Tyr Ala Leu Gly Phe Gln His Ala Leu Ser Glu

1 5 10 15

Lys Ala Met Ala Arg Leu Gln Glu Leu Leu Thr Val Ser Glu

20 25 30

<210> 442

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-8

<400> 442

Gly Phe Thr Thr Ser Ile Leu Gln Tyr Glu Asn Ser Ile Met Leu Gln

1 5 10 15

Asp Gly Arg Leu Leu Ser Ser Thr Leu Ser Leu Ser Ser Asn

20 25 30

<210> 443

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-9

<400> 443

Tyr Ser Arg Val Val Phe Gln Met Pro His Gln Glu Ile Val Asp Asn

1 5 10 15

Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg

20 25 30

<210> 444

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-10

<400> 444

Ala Phe Ala Ala Ala Tyr Phe Glu Ser Leu Leu Glu Lys Arg Glu Met

1 5 10 15

Phe Thr Ser Ser Arg Met Ser Ser Phe Asn Arg His Met Lys

20 25 30

<210> 445

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-11

<400> 445

Asn Ser Pro Leu Pro Phe Gln Trp Arg Ile Thr His Ser Phe Arg Arg

1 5 10 15

Ser Ile Ala Gly Phe Val Ala Ser Ile Asn Glu Gly Met Thr

20 25 30

<210> 446

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-12

<400> 446

Ser Ser Tyr Phe Val Leu Ala Asn Gly His Ile Leu Pro Asn Ser Trp

1 5 10 15

Glu Glu Ala Tyr Thr Phe Glu Gly Ala Arg Tyr Tyr Ile Asn

20 25 30

<210> 447

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-13

<400> 447

Leu Gln Lys Val Gln Phe Glu Lys Val Ser Ala Leu Ala Asp Leu Leu

1 5 10 15

Glu Arg Leu Ala Tyr Leu His Ala Arg Leu Arg Glu Leu Leu

20 25 30

<210> 448

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-14

<400> 448

Ser His Ser Tyr Val Leu Val Thr Ser Leu Asn Leu Ser Tyr Asp Phe

1 5 10 15

Met Phe Gln Glu Ala Leu Lys Leu Lys Val Ala Glu Leu Val

20 25 30

<210> 449

<211> 30

<212> PRT

<213> Artificial sequence

<220>

<223> BCV900-6-15

<400> 449

Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys Gln

1 5 10 15

Thr Leu Ile Tyr Tyr Val Asp Glu Lys Ala Pro Glu Phe Ser

20 25 30

Claims (11)

1. A pharmaceutical composition or a pharmaceutical kit, comprising a polypeptide consisting of an amino acid sequence selected from any one of SEQ ID NOs: 130, 121, 131, 124, 134 and 126. 2. A pharmaceutical composition or a pharmaceutical kit comprising a nucleic acid encoding a polypeptide, wherein the polypeptide consists of an amino acid sequence selected from any one of SEQ ID NOs: 130, 121, 131, 124, 134 and 126. 3. A pharmaceutical composition or a pharmaceutical kit comprising a group of two or more polypeptides, or a nucleic acid encoding a group of multiple polypeptides, wherein each polypeptide or each polypeptide in the group encoded by the nucleic acid consists of an amino acid sequence selected from any one of SEQ ID NO: 130, 121, 131, 124, 134 and 126. 4. The pharmaceutical composition or pharmaceutical kit of claim 3, wherein the group of polypeptides, or the group of polypeptides encoded by the nucleic acid, comprises polypeptides having at least two different amino acid sequences selected from SEQ ID NO: 130, 121, 131, 124, 134 and 126. 5. A pharmaceutical composition or pharmaceutical kit as described in claim 3, wherein the group of polypeptides, or the group of polypeptides encoded by the nucleic acid, comprises polypeptides having at least three different amino acid sequences selected from SEQ ID NO: 130, 121, 131, 124, 134 and 126. 6. The pharmaceutical composition or pharmaceutical kit according to claim 3, wherein the group of polypeptides, or the group of polypeptides encoded by the nucleic acid, comprises six peptides having the amino acid sequences of SEQ ID NOs: 130, 121, 131, 124, 134, and 126. 7. Use of the pharmaceutical composition or pharmaceutical kit according to any one of claims 1 to 6 in the preparation of a vaccine, wherein the vaccine is used to provide immunotherapy or induce a cytotoxic T cell response in a subject. 8. The use according to claim 7, wherein the vaccine is used to treat cancer. 9. The use according to claim 8, wherein the cancer is colorectal cancer, ovarian cancer or breast cancer. 10. The use according to claim 8 or 9, wherein the vaccine or the pharmaceutical composition or the pharmaceutical kit is combined with a chemotherapeutic agent, a targeted therapeutic agent or a checkpoint inhibitor. 11. The use according to any one of claims 7 to 9, wherein the use is for the preparation of a medicament for preventive treatment.